bmj open...for peer review only 5 introduction korean statistical data show that the prevalence of...

For peer review only

The effectiveness and safety of moxibustion as an adjunct or benign prostatic hyperplasia with lower urinary tract

symptoms: a protocol for a parallel-group, randomized, controlled pilot trial

Journal: BMJ Open

Manuscript ID: bmjopen-2015-008338

Article Type: Protocol

Date Submitted by the Author: 28-Mar-2015

Complete List of Authors: Lee, Hye-Yoon; Pusan national university Korean medicine hospital, Internal medicine Nam, Jong-Kil; Pusan National University Yangsan Hospital, Urology Lee, Sang-Don; Pusan National University Yangsan Hospital, Urology Lee, Dong-Hoon; Pusan National University Yangsan Hospital, Urology Han, Ji-Yeon; Pusan National University Yangsan Hospital, Urology Yoon, Young-Ju; Pusan National University Korean medicine Hospital, Internal medicine Lee, Ji-Hye; Pusan National University Korean medicine Hospital, Internal medicine

Park, Hye-lim; Pusan National University Korean medicine Hospital, Internal medicine Park, Seong-Ha; Pusan National University Korean medicine Hospital, Internal medicine Kwon, Jung-Nam; Pusan National University Korean medicine Hospital, Internal medicine

<b>Primary Subject Heading</b>:

Urology

Secondary Subject Heading: Urology

Keywords: Prostate disease < UROLOGY, moxibustion, Kidney & urinary tract disorders < UROLOGY, integrative medicine, lower urinary tract symptoms

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

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The effectiveness and safety of moxibustion as an adjunct or benign prostatic hyperplasia with lower

urinary tract symptoms: a protocol for a parallel-group, randomized, controlled pilot trial

Hye-Yoon Lee1, 2

, Jong-Kil Nam3, 4

, Sang-Don Lee3, 4

, Dong-Hoon Lee3, 4

, Ji-Yeon Han3, 4

, Young-Ju Yoon1, 5

, Ji-

Hye Lee1, 6

, Hye-lim Park1, 2

, Seong-Ha Park1, 5

, Jung-Nam Kwon1, 5*

1Department of Internal Medicine, Pusan National University Korean Medicine Hospital, Yangsan, 626-770,

South Korea

2Department of Korean Medicine, School of Korean Medicine, Pusan National University, Yangsan, 626-870,

South Korea

3Department of Urology, Pusan National University Yangsan Hospital, Yangsan, 602-739, South Korea

4Department of Urology, School of Medicine, Pusan National University, Yangsan, 626-770, South Korea

5Division of Clinical Medicine, School of Korean Medicine, Pusan National University, Yangsan, 626-870,

South Korea

6Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, 626-

870, South Korea

Authors’ email addresses:

Hye-Yoon Lee: [email protected]

Jong-Kil Nam: [email protected]

Sang-Don Lee: [email protected]

Dong-Hoon Lee: [email protected]

Ji-Yeon Han: [email protected]

Young-Ju Yoon: [email protected]

Ji-Hye Lee: [email protected]

Hye-lim Park: [email protected]

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Seong-Ha Park: [email protected]

*Corresponding author: Jung Nam Kwon, KMD, PhD

Address: Department of Korean Medicine, School of Korean Medicine, Pusan National University, 20 Gueno-ro,

Mulgeum-eup, Yangsan, 626-770, Gyeongnam, South Korea

Telephone: 82-55-360-5666

Fax: 82-55-360-5736

Email: [email protected]

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ABSTRACT

Introduction

This study aims to assess the feasibility of moxibustion as a supplementary intervention for patients with benign

prostate hyperplasia (BPH) accompanying moderate to severe lower urinary tract symptoms (LUTS).

Methods and analysis

A total of 60 patients diagnosed with benign prostatic hyperplasia by a urologist based on prostate size, prostate-

specific antigen (PSA), and clinical symptoms will participate of their own free will, and urologists will monitor

patients and evaluate their symptoms. The patients will be randomized into a conventional group or integrative

group with a 1:1 allocation according to computer-generated random numbers concealed in opaque, sealed,

sequentially numbered envelopes. Watchful waiting or oral medication including alpha-blocker, 5-alpha-

reductase inhibitors (5-ARIs) or anti-muscarinic drugs will be offered as a conventional treatment. Integrative

treatment will include moxibustion therapy in addition to the conventional treatment. The moxibustion therapy

will be conducted twice per week for four weeks on the bilateral acupoints SP6, LR3 and CV4 by a qualified

Korean medical doctor (KMD). The primary outcome will be the international prostate symptom score (IPSS)

after 8 sessions. The secondary outcomes will be the post-void residual urine volume (PVR), the maximum

urinary flow rate (Qmax), IPSS, the results of a short-form 36-question health survey (SF-36) after 12 weeks

and the patients' global impression of changes (PGIC) at each visit.

Ethics and dissemination

Written informed consent will be obtained from all participants. This study was approved by the IRBs of both

PNUYH and PNUKH.

Trial registration number: clinicaltrials.gov. NCT02051036 (Date: 01/26/2014)

Strengths and limitations of this study

� The design of this clinical trial is based on an experts’ conference with KMDs, urologic doctors (UDs),

and an Eastern-Western integrative medicine specialist who has both MD and KMD licenses to

develop an optimal integrative treatment.

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� Optimal conventional oral medications and a customized number of moxibustion layers for each

patient are used to reflect the real clinical setting.

� This study’s results can serve as a basis for further large studies or studies of intractable urinary

disorders.

� The statistical power of the study may be low due to the small sample size.

� Practitioners and patients cannot be blinded.

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INTRODUCTION

Korean statistical data show that the prevalence of benign prostatic hyperplasia (BPH) in men over 65 years was

17.9% in 20111, and BPH ranked 25

th among male outpatient visits by frequency of disease in 2013

2.

BPH causes lower urinary tract symptoms (LUTS) by directly disturbing the bladder outlet or increasing the

tension and resistance of smooth muscles3. For treatment, watchful waiting at the beginning and behaviour

modification with oral medication are recommended3 4

, and these methods have proved effective in improving

LUTS, urinary flow rate and post-void residual urine in many previous studies5-7

.

However, this conventional treatment is limited by certain side effects. For alpha-blockers, rhinitis (6.6%),

dizziness (4.4%)5, abnormal ejaculation (2.1-2.8%)

5 8, and faintness (5.4%)

9 as an indicator of cardiovascular

side effects of tamsulosin have been observed. Additionally, abnormal ejaculation (14.2%-28.1%) caused by

silodosin8 10

; cardiovascular adverse events (5.7% hypertension, 3.9% non-hypertension)11

and mild dizziness

(13.9%)9 caused by alfuzosin; severe dizziness leading to drug-suspension (2.0%) caused by terazosin

12; and

erectile dysfunction (3.56%), dizziness (4.41%), postural hypotension (4.03%) and asthenia (4.08%)13

caused by

doxazosin have been verified. In addition, erectile dysfunction (4.53%), dizziness (2.33%), postural hypotension

(2.56%), decreased libido (2.36%) and abnormal ejaculation (1.78%)13

caused by finasteride and dry mouth

(24%), dyspepsia (5%), back pain (5%), micturition disorder (5%), constipation (3%), and urinary retention

(3%)14

caused by tolterodine have been shown to occur. In particular, when two or more types of these

medications are combined, each side effect is expected; thus, careful use only for patients with moderate to

severe BPH is recommended4.

To overcome this limitation, many studies investigating complementary and alternative medical (CAM)

treatment have been conducted, but the 2011 American Urological Association’s (AUA) guideline reported that

no definite evidence exists to recommend CAM treatment due to the lack of quality and quantity of CAM

studies of BPH3.

In contrast, clinical studies of acupuncture or herbal medication for BPH with LUTS have been consistently

performed15-19

and have demonstrated the effectiveness of these methods. Moxibustion has been shown to be

effective in treating urinary disorders20

, but well-designed clinical trials to prove its effectiveness are lacking.

Therefore, we designed a clinical trial to evaluate the effectiveness and safety of moxibustion treatment to

develop an optimal integrative treatment that can be accepted by both MDs and KMDs in the present medical

system. The design of this clinical trial is based on a literature survey and an experts’ conference with KMDs,

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urologic doctors (UDs), and an Eastern-Western integrative medicine specialist who has both MD and KMD

licenses. This study is a randomized controlled trial with a parallel-group, 1:1 allocation, exploratory and

pragmatic design.

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METHODS AND ANALYSIS

1. Aims

The present study aims to evaluate the feasibility and the effect-size for superiority-verification research on the

effectiveness and safety of integrative treatment compared with conventional treatment for patients with BPH

accompanying LUTS. This is a single-centre, assessor- and analyser-blinded, parallel-group, 1:1 allocation,

pragmatic randomized controlled study.

2. Recruitment

Notices were posted in front of the Pusan National University Yangsan Hospital (PNUYH) urologic office and

the Pusan National University Korean Medicine Hospital (PNUKH) genitor-urinary clinic office, and

advertising for the study was also placed on the internet homepage of PNUKH. A UD will confirm the diagnosis

of benign prostatic hyperplasia and needlessness of surgical treatment for patients who volunteer to participate.

A KMD will thoroughly examine all inclusion/exclusion criteria and explain the trial to eligible patients. When

the patient decides to participate in the study, the KMD will obtain written informed consent, and a baseline

assessment will be performed. The progress of the study will consist of a screening phase, a treatment phase and

follow-up. A more detailed description of the study is shown in figure 1. The time schedule for participation is

shown in table 1.

3. Study design

Randomization and allocation concealment

A statistician who does not take part in this study will place the computer-generated random list into each

double-layered opaque envelope, seal it and write the numbers in sequence. A practitioner will give the envelope

to the patient according to the visit order and open it with the patient.

4. Patients

4.1. Sample size

The sample size calculation was not performed based on a power calculation because this is a pilot study. The

sample size was determined based on estimates of the number of patients expected to participate and the

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minimum number to evaluate the pragmatic purpose of this trial. Thus, a sample size of 30 per group and total

number of 60 will be included, which is larger than the minimum number required for pilot studies21

.

4.2. Inclusion criteria

1. Male patients aged 20-80 years diagnosed with BPH with a prostate size over 20 gm

2. IPSS score ≥ eight

3. Written informed consent obtained

4. Patient must understand and answer the IPSS

4.3. Exclusion criteria

1. Prostate or bladder malignancy

2. Received herbal medication for lower urinary tract symptoms within one week

3. History of a brain disease that can cause urinary difficulty

4. Difficulty answering IPSS due to cognitive impairment

5. Signs of acute urinary tract infection

6. Diabetic mellitus

7. Neurogenic bladder

4.4. Drop-out criteria and process of management

4.4.1. Definition of drop-out

Completed cases will be defined as patients who finish the treatment progress and follow-up. Patients who

cannot complete the study due to side effects or for other reasons will be considered drop-out cases.

4.4.2. Drop-out criteria

The researcher may stop treatment and observation of a patient according to prescribed criteria, and the patient

can drop-out voluntarily at any time. The drop-out criteria are as follows.

1. Violation of inclusion/exclusion criteria

2. Serious adverse events or adverse events making a patient wish to drop out

3. Severe systemic disease that was not recognized at baseline

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4. Patients or a legal representative demand cessation of the trial due to unsatisfying effects or withdrawal of

consent

5. Trial compliance of less than 80%

6. Protocol violation of patient or researcher

7. Difficulty conducting moxibustion due to newly developed disease or uncooperative manner

8. Patients not replying to outcome measures

9. Patient’s desire or UD’s recommendation for surgical treatment (including minimally invasive therapies)

4.4.3. Management process

The drop-out date, time and reason will be recorded on the end report. Patients can drop out voluntarily for any

reason, at any time, and are not required to submit a reason. The researcher should make every effort to follow

up with patients who have dropped out and record the reason for drop-out or the reason for not being able to

determine a drop-out cause.

5. Blinding of outcome assessors and data analysers

The practitioner and patients cannot be blinded because this is an open-label study for moxibustion treatment.

Assessors and analysers will be blinded. Urodynamic testing will be performed by an assistant who does not

take part in the trial, and participants will be asked not to reveal their allotted group to the assistant. Subjective

outcomes will be recorded by the patient. The groups will be marked “A” and “B” when the data are sent to the

statistician to ensure that the groups are not recognized as the control group and experimental group. Un-

blinding of the assessors will be permissible only in the case of a serious adverse event.

6. Interventions

6.1. Conventional treatment protocol

The conventional treatment will be set as the optimum treatment for each patient to develop a reasonable

integrative treatment protocol22

.

The optimum treatment for each patient will be based on the UD’s opinion. The UD will discuss behavioural

modifications, such as water intake, with the patient. Watchful waiting will be used for patients without renal

insufficiency, urinary retention, recurring infection or complications of bladder-outlet obstruction (BOO). Oral

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medications will be prescribed when no therapeutic effect is observed after watchful waiting, and the

medications will be selected in consideration of overactive bladder, prostate size and prostate-specific antigen

(PSA). Preferentially, an alpha-blocker, such as alfuzosin, doxazosin, tamsulosin or terazosin, will be used for

functional symptom mitigation. 5-ARIs, such as dutasteride and finasteride, will be used when the prostatic

volume is > 40 ml or PSA > 1.4 ng/ml. For cases of a high risk of BPH progression, prostate ≥ 30 mg or PSA ≥

1.5 ng/ml, a combination of an alpha-blocker and a 5-ARI will be used. Anticholinergic agents, such as

tolterodine, will be prescribed for patients with overactive bladder but will need to be monitored for patients

with ≥ 250 ml post-void residual urine. The conventional treatment components can be changed at the discretion

of the UD because this research is a pragmatic study to evaluate the effectiveness and safety of additional

moxibustion therapy and the conventional treatment will still be maintained for long-term follow-up3 4

.

6.2. Integrative treatment protocol

Moxibustion therapy will be added to the conventional treatment described in section 6.1 twice per week for

four weeks. The moxibustion therapy will be conducted by a skilled KMD who has at least two years’

experience in the clinic. The timeframes of the conventional treatment group (CG) and the integrative treatment

group (IG) are shown in figure 2. Both the apparatus type and mini-pillar type moxibustion will be used.

The apparatus types are a Hatnim-moxa apparatus (Bosungsa, Incheon, South Korea) and a moxa pillar

(Bosungsa, South Korea) that generates 65-70 °C of heat. Moxibustion will be conducted at acupoints CV4 on

one layer of gauze (figure 3) for 30 minutes. This acupoint was selected based on the KM theory20 23

and

previous clinical studies17

24

. Additional gauze will be offered layer by layer when the patient requests it due to

intolerable heat. This apparatus-moxibustion will be stopped if the patient complains of intolerable heat even

after the additional gauze is offered more than three times. If the patient cannot feel any heat once the moxa

pillar is totally burned, the apparatus-moxibustion will be conducted one more time; the procedure can be

performed one more time as before, but the number of apparatus-moxibustion applications cannot exceed three.

The therapy can be stopped if a second-degree or higher burn occurs even before completing eight treatment

sessions.

Kanghwa mini-moxa of “lowest” intensity, which generates heat of approximately 45 °C, will be used for mini-

pillar-type indirect moxibustion. Mini-moxa will be conducted at bilateral acupoints SP617 20 25

and LR320 26 27

(figure 4). The mini-moxa will be removed when totally burned, which takes approximately 5 minutes, but it

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may be removed if the patient complains of intolerable heat. The mini-moxa will not be repeated on the acupoint

on which moxibustion was stopped per the patient’s request. Repetitive mini-moxa will be performed on the

acupoints at which the patient did not feel heat and completed prior mini-moxa for the entire burning period, up

to a maximum of seven times on each point. Beginning with the second session, the treated region will be

checked and further mini-moxa will not be allowed on an acupoint where a second-degree or higher burn

occurred. In this case, the mini-moxa will be re-started after the burn is completely healed.

The treatment session of twice per week for 4 weeks was determined based on the studies of Yang T28

, Liu QG29

and Wang Y24

, which reported the effective results and clinical experiences of two KMDs. The number of

performed moxibustion treatments will be recorded in both the electronic medical record (EMR) and case report

form (CRF) at every visit in adherence with intervention protocols.

It is reasonable to stop moxibustion therapy if a second-degree or higher burn occurs according to KM theory30

,

and in this case, the patient will not be considered a study drop-out. However, if a patient cannot continue the

treatment because of discomfort from the moxibustion smoke, allergic response or pigmentation from the moxa-

soot, he cannot be regarded as having completed the trial.

6.3. Prohibited or allowed parallel medical treatments

Flexible oral medications according to the discretion of the UD's opinion are allowed to offer the best treatment

for each patient; thus, the medications will not be fixed without variation. All types of medication therapy based

on AUA guidelines and the Korean prostate society guideline will be allowed.

Surgical treatment, including transurethral resection of the prostate (TURP), transurethral incision of the

prostate (TUIP), abdominal prostatectomy, minimally invasive therapy using a laser, transurethral needle

ablation of the prostate (TUNA), and transurethral microwave thermotherapy (TUMT), are prohibited; therefore,

patients who want or are recommended for such therapies cannot participate in this trial.

6.4. Treatment of adverse events

We will disinfect and dress the wound when a second-degree or higher burn occurs and will refer the patient to

dermatology to receive proper treatment when a third-degree or higher burn occurs.

7. Outcome measures

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7.1 Primary outcome measure

The IPSS after 8 sessions will be the primary outcome measure. IPSS was developed by the AUA in 1992, and a

question regarding quality of life (QoL) was later added31

. The Korean version was validated in 199632

. IPSS

consists of seven sub-themes of incomplete emptying, frequency, intermittency, urgency, weak stream, straining

and nocturia. The severity scoring is as follows: 0-7, mildly symptomatic; 8-19, moderately symptomatic; and

20-35, severely symptomatic BPH. The separate QoL question requires the respondent to select a QoL category

ranging from zero (delighted) to six (terrible).

7.2 Secondary outcome measure

7.2.1. Patient’s global impression of changes (PGIC)

The PGIC will be recorded for each patient at every visit after the first treatment. PGIC is a scoring system used

to evaluate the level of change from the beginning of the treatment, either conventional or integrative, to the

time of the PGIC check. This scale considers limitations of physical activity, symptoms, emotions and QoL in

general. The scoring is as follows: no change (or condition has become worse), 1; almost the same, hardly any

change at all, 2; slightly better, but no noticeable change, 3; somewhat better, but the change has not made any

real difference, 4; moderately better and a slight but noticeable change, 5; better and a definite improvement that

has made a real and worthwhile difference, 6; a great deal better and a considerable improvement that has made

a substantial difference, 7. In a similar way, each patient will be asked to circle one of the numbers 0 (much

better) to 10 (much worse) written on a straight line that represents the change from the beginning to the time of

evaluation33

.

7.2.2. The short-form 36-question health survey (SF-36)

The SF-36 will be checked at the baseline, after 4 sessions, after 8 sessions and after 12 weeks from the baseline.

The SF-36 is a commonly used scale to evaluate health-related quality of life (HRQOL). This scale consists of

physical function, physical role capability, bodily pain, general health perceptions, vitality, social role capability,

emotional role capability and mental health34

.

7.2.3. The maximum urinary flow rate (Qmax)

Qmax changes from baseline to 12 weeks will be used as an objective outcome measure. Urodynamic study is

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an invasive method to obtain objective and quantitative data on bladder-outlet function and storage function.

Patients will attend the study when they feel a “normal” desire to urinate. The velocity of the external urine

stream will be automatically obtained by a calculation using the voided volume and time35

.

7.2.4. Post-void residual urine volume (PVR)

PVR changes from baseline to 12 weeks will be evaluated because PVR increases when bladder-outlet function

is incomplete35

. PVR will be checked by ultrasonography immediately after the urodynamic study.

7.2.5. Long-term IPSS

The IPSS will be checked 12 weeks after the beginning of the study, after 8 weeks of completed moxibustion

therapy, to evaluate the persistency of the effects of moxibustion therapy. This period of 12 weeks was

determined based on a previous study26, the clinical experiences of two KMDs, and the optimum follow-up

period recommended in conventional treatment guidelines60 70-73

.

7.3 Adverse events

At every visit, patients will be asked if adverse effects have developed and, if so, what types of adverse effects.

In particular, second-degree or higher burns and allergic responses of the skin or whole body will be examined

thoroughly, and other types of discomfort will be checked.

8. Data collection

Subjective outcome measurements will be checked for each patient, and objective outcome measurement data

will be preserved in both their original form and as an EMR. These data will be written on the CRF by a

certificated clinical research coordinator (CRC). To promote patient retention and completion of follow-up, an

honorarium will be provided with a differential rate according to the patients' participation.

9. Statistical analysis

9.1. Analysis of efficacy

Both intention-to-treat (ITT) and per-protocol (PP) analyses will be performed. The last observation carried

forward (LOCF) method will be used for missing data in ITT analysis. The paired t-test will be used for

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intragroup before/after treatment comparisons. The independent t-test will be used for intergroup comparisons.

For non-parametric data, the Wilcoxon signed-rank test for intragroup and the Wilcoxon rank-sum test for

intergroup test will be used. Categorical data, such as adverse effects, will be investigated by calculating the

occurrence rate of adverse events for each group and then performing analysis with the chi-square test or

Fisher’s exact test. If statistically significant differences between two groups are observed or covariance is

expected, analysis of covariance (ANCOVA) will be used. All of the statistical analysis will be done with two-

tailed tests, and the significance level will be set as 0.05.

10. Safety

Expected adverse events, such as burns and allergic responses, will be recorded along with their modality, date

of occurrence, and duration. Patients will report other unexpected adverse events freely. The severity of the

adverse events will be categorized according to the WHO 5-grade performance status classification as follows: 0,

able to carry out all normal activity without restriction; 1, restricted in strenuous activity but ambulatory and

able to carry out light work; 2, ambulatory and capable of all self-care but unable to carry out any work

activities and up and about more than 50% of waking hours; 3, symptomatic and in a chair or in bed for greater

than 50% of the day but not bedridden; 4, completely disabled, unable to carry out any self-care; totally

confined to bed or chair. The cause-and-effect relation between the intervention and adverse events will be

assessed according to the WHO-Uppsala Monitoring Centre (UMC) causality categories of 1, certain; 2,

probable/likely; 3, possible; 4, unlikely; 5, conditional/unclassified; 6, unassessable/unclassifiable.

To minimize the expected adverse events, we will describe the risk of adverse events to patients who have prior

allergic responses to moxibustion therapy, allergic rhinitis or allergic conjunctivitis. Patients will be informed to

notify the practitioner if they experience such symptoms during the treatment to receive proper and prompt

treatment. The treatment will be performed in a well-ventilated room, and a mask will be offered to cover the

patient’s mouth and nose. To prevent burns, patients will be educated about indirect moxibustion therapy and its

precautions and informed to notify the practitioner promptly if they feel intolerable heat and wish to stop the

treatment. The principal investigator (PI) will describe and assess all of the symptoms that occur during the

clinical trial and will report to the institutional review board (IRB) to determine whether to continue or stop the

study when serious adverse events occur.

Patients who suffer from adverse events will be treated as described in section 6.4. Additionally, patients who

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suffer harm from this trial participation will be cared for through insurance. All patients will be informed of and

sign off on the “regulation concerning subject compensation”, including detailed descriptions of this regulation.

11. Monitoring

The independent data monitoring committee (DMC), composed of one KMD and one clinical research expert,

will examine the process of progress and whether the trial follows the study plan, the standard guidelines, and

clinical-trials management criteria and other related standards. Monitoring will be conducted by regular visits

and phone calls. The DMC will check the original record and case report forms. If any problem is found, the

DMC will discuss this with the PI. If any serious problems that could threaten the security of patients are found,

the DMC will discuss this with the IRB and PI. The PI will make the final decision as to whether to continue or

to terminate the trial, and the IRB can order the PI to terminate the trial in the case of a serious problem.

12. Ethical considerations and dissemination

12.1. Written informed consent and study approval

This study was approved by the IRBs of both PNUYH and PNUKH. A signed informed consent will be

submitted from each patient to the practitioner. If any changes to the inclusion/exclusion criteria, outcome

measure methods or data analysis are demanded, the decision will be made through a discussion between the

UD and KMD. The changed contents would need to be reapproved by the IRB and reflected in the patient-

explanation and study registration (clinicaltrials.gov), and a new consent from the patient would need to be

obtained.

12.2. Private information protection

Collected data from patients will be safeguarded with specific serial numbers without any personally identifiable

information so that nobody can recognize the patients except a security manager who has a code-table.

Computer-stored personal information will be secured using a password, and all matters related to security will

be supervised by the PI. Publication will not include any personally identifiable information, and data will be

treated anonymously. Strict security is assured even in a case of a patient dropping out mid-study and after the

end of the study.

Data used for the study will be disposed of after the collection of materials for a research paper. Computer

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storage files will be deleted and documents will be shredded on 31st November, 2017.

The PI, a monitor and an inspector can read the patients’ records for the purpose of monitoring and progress

oversight in terms of laws and ethics. These data will be stored securely in the National Clinical Research

Center for Korean Medicine. This matter will be explained to patients, who will also be provided a written

explanation.

12.3. Dissemination

The trial results will be disseminated through open-access journals and conferences.

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DISCUSSION

This is the first study protocol of a randomized controlled trial in Korea to evaluate the effectiveness and safety

of moxibustion as a complement to conventional therapy for patients with BPH accompanying LUTS.

The medical system of South Korea has been maintained as a dualized system since the revival of KMD by the

enactment of the National Medical Insurance Act in 1951. This system has had some negative aspects, such as

the incautious use of medicine combinations and distrust between the two medical fields; however, it has had

some positive aspects as well, including providing patients with a large variety of treatment choices36

. Therefore,

the necessity of integrative medicine has been propounded steadily to establish a new medical system combining

the advantage of Western and Korean medicine37

.

This study was designed as an investigation of add-on treatment without a placebo control because methods of

additional alternative treatments in conjunction with the conventional treatment are considered appropriate in

light of the medical ethics and medical treatment system38 39

. Despite relatively acceptable rates of adverse

events, increased side effects caused by the combination of different types of oral drug4 and by patient

vulnerability factors, such as ageing and underlying disease, still must be investigated. Therefore, the

effectiveness and safety of adjuvant treatments should be evaluated, after which the adjuvant treatment may be

considered for intractable urinary disorders including interstitial cystitis and chronic prostatitis. Additionally, a

pragmatic design is used to improve applicability to the clinical field and decision making40 41

. Thus, we set

broad inclusion/exclusion criteria and flexible interventions allowing for different treatment regimes according

to each patient’s medical condition. In addition, conventional oral medication is not restricted to one type

considering the pragmatic purpose and the study ethics.

This study has some limitations. The prostate size is not included as an outcome measurement because this

study aims to assess the effectiveness of treatment according to the functional improvement of LUTS. Therefore,

studies evaluating the effect of the combined treatment on prostate size should be conducted after the LUTS-

reduction effect is demonstrated. Future power analysis studies should be performed by determining the effect

size based on the results of this study, and cost-effectiveness studies should be performed to provide important

details for decision-makers.

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TRIAL STATUS

This study is currently in the recruiting phase. The first patient enrolled on March 10th

, 2014, and the article

including results is expected in approximately 2016.

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Acknowledgements

This study was supported by the Korea Institute of Oriental Medicine (K14273).

Contact name: Dal-Seok Oh, Senior Research Fellow

Address: 1672 Yuseong-daero, Yuseong-gu, Daejeon 305-811, Korea

TEL: +82-42-861-1994

E-mail: [email protected]

Contributors

JNK, SDL and JGN conceived the study. JNK, SDL, JKN, JYH, YJY and HYL initiated the study design, and

DHL, SHP, JHL and HLP helped with its implementation. JKN, DHL, JHY and HYL performed the intervention

and discussed the optimal complementary medicine. HYL drafted the study protocol manuscript. All authors

contributed to the refinement of the study protocol and approved the final manuscript.

Competing interests

None

Access to data

The data from this trial will be accessible by contacting the corresponding author.

Ethics approval

The study was approved by IRBs of both Pusan National University Korean Medicine Hospital (IRB approval

number 2013021) and Pusan National University Yangsan Hospital (IRB approval number 03-2013-013).

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APPENDIX

Table 1. Trial progress

Period Screening Active treatment F/U

Visit Screening 1 2 3 4 5 6 7 8 9* 10

Week 0 1 2 3 4 12

Consent ●

Demographic survey ●

Medical history ● ○ ○ ○ ○ ○ ○ ○ ○ ● ●

Vital signs ● ○ ○ ○ ○ ○ ○ ○ ○ ●

Physical examination ●

Conformity

assessment

●

Check PSA ●

Check prostate size

(TRUS)

●

Inclusion/exclusion

criteria

●

Inform patient of the

visit schedule

● ○ ○ ○ ○ ○ ○ ○ ○ ○

Randomization ●

Moxibustion ○ ○ ○ ○ ○ ○ ○ ○

IPSS ● ○ ● ●

SF-36 ● ○ ● ●

PGIC ○ ○ ○ ○ ○ ○ ○ ● ●

Qmax ● ●

PVR ● ●

FVC ● ●

Adverse event

monitoring

○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Final compliance

assessment

●

○: integrative group

●: both integrative group and conventional group

*visit 9: 1-3 days after visit 8

PSA: prostate specific antigen; TRUS: transrectalultrasonography; IPSS: international prostate

symptom; short-form 36-question health survey; PGIC: patients' global impression of changes; Qmax:

maximum urinary flow rate; PVR: post-void residual urine volume; FVC: frequency-volume chart

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Table 2. International prostate symptom score

Not

at a

ll

Les

s th

an

1 t

ime

in 5

Les

s th

an

hal

f th

e ti

me

Ab

out

hal

f th

e ti

me

Mo

re t

han

hal

f th

e ti

me

Alm

ost

alw

ays

Incomplete emptying

Over the past month, how often have you had a sensation of

not emptying your bladder completely after you finish

urinating?

0 1 2 3 4 5

Frequency

Over the past month, how often have you had to urinate

again less than two hours after you finished urinating?

0 1 2 3 4 5

Intermittency

Over the past month, how often have you found you stopped

and started again several times when you urinated?

0 1 2 3 4 5

Urgency

Over the last month, how difficult have you found it to

postpone urination?

0 1 2 3 4 5

Weak stream

Over the past month, how often have you had a weak

urinary stream?

0 1 2 3 4 5

Nocturia

No

ne

1 t

ime

2 t

imes

3 t

imes

4 t

imes

5 t

imes

or

mo

re

Over the past month, how many times did you most

typically get up to urinate from the time you went to bed

until the time you got up in the morning?

0 1 2 3 4 5

Quality of life due to urinary symptoms

Del

ighte

d

Ple

ased

Most

ly

sati

sfie

d

Mix

ed –

ab

ou

t

equ

ally

Most

ly

dis

sati

sfie

d

Un

hap

py

Ter

rib

le

If you were to spend the rest of your life with your

urinary condition the way it is now, how would you

feel about that?

0 1 2 3 4 5 6

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Total score: 0-7, mildly symptomatic; 8-19, moderately symptomatic; 20-35, severely symptomatic.

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Figures

Figure 1. Trial flowchart

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Figure 2. Timeframe of the integrative treatment group (IG) and conventional treatment group (TG).

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Figure 3. Apparatus-type moxibustion on CV4

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Figure 4. Mini-pillar-type moxibustion on bilateral SP6 and LR3

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Data Category Information

Primary Registry and Trial Identifying

number

NCT02051036

Date of Registration in Primary

Registry

01/26/2014.

Secondary Identifying Numbers NC1307

Source(s) of Monetary or Material

Support

Korea Institute of Oriental Medicine

Primary Sponsor Korea Institute of Oriental Medicine

Secondary Sponsor(s) National Clinical Research Center

Contact for Public Queries Corresponding author

Contact for Scientific Queries Corresponding author

Public Title Moxibustion as a complement to benign prostatic hyperplasia accompanying

lower urinary tract symptoms

Scientific Title The effectiveness and safety of moxibustion as a complement for benign prostatic

hyperplasia with lower urinary tract symptoms

Countries of Recruitment Korea, Republic of

Health Condition(s) or Problem(s)

Studied

Benign prostatic hyperplasia with lower urinary tract symptoms

Intervention(s) Treatment: moxibustion plus usual care

Control: usual care alone

Key Inclusion and Exclusion Criteria Ages eligible for study: between 20 and 80 years; sexes eligible for study: male;

accepts healthy volunteers: no

Inclusion criteria:

1. Male patients diagnosed benign prostate hyperplasia aged from 20 to 80 years;

prostate size over 20 gm

2. Greater than or equal to a score of eight on the IPSS

3. Submit written consent

4. Patients who can understand and answer the IPSS

Exclusion criteria:



3. History of brain disease which can cause urinary difficulty 4. Difficulty answering IPSS due to cognitive impairment




Study Type Randomized controlled trial, parallel, 1:1 ratio, pilot study

Allocation: randomized; intervention model: parallel assignment

Primary purpose: international prostate symptom score

Date of First Enrolment 2014/03/10 Target Sample Size 60

Recruitment Status recruiting

Primary Outcome(s) International prostatic symptom score

Key Secondary Outcomes Maximum uroflow rate, post-void residual urine

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Application for participation

Confirm diagnosis of BPH (PSA, TRUS, IPSS)

Examination by a

urologist

Exclusion: unconfirmed BPH, IPSS<8

Examination by KMD

Full eligibility screening and written informed consent

Confirm enrolment and baseline assessment

Group allocation Allocation

Follow-up

Outcome assessment at 4

Outcome assessment at 12 weeks

Analysis Analysis

Treatment Integrative group (n=30)

conventional treatment, moxibustion

Conventional group (n=30)

conventional treatment

Exclusion: neurogenic bladder, acute urinary tract

infection, recommended surgical treatment

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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 ______3_______

2b All items from the World Health Organization Trial Registration Data Set ______29______

Protocol version 3 Date and version identifier ______3_______

Funding 4 Sources and types of financial, material, and other support ______21______

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors ______21______

5b Name and contact information for the trial sponsor ______21______

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

______21______

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)

______21______

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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

______5_______

6b Explanation for choice of comparators ______5______

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)

______6_______

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

______7_______

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)

______8_______

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

administered

______9______

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)

______10______

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 ______11______

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)

______7______

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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

______7______

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______7___ ___

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

______7__ ____

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

_______7______

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

interventions

_______7______

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

assessors, data analysts), and how

_______9______

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

allocated intervention during the trial

_______9______

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

_____13, 15_____

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

_______13______

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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

______16_____

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

______13______

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ______13______

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)

______13______

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

______15______

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

______15______

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

______14______

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

from investigators and the sponsor

______15______


Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ______21______

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)

______15______

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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)

______15______

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

studies, if applicable

_____none_____

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

______15______

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site ______21_______

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

______21______

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

______15______

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

______16______

31b Authorship eligibility guidelines and any intended use of professional writers ______16______

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code ______16______

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates ___ ___

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

___ __

*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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Moxibustion as an adjuvant for benign prostatic hyperplasia with lower urinary tract symptoms: a protocol for a parallel-

group, randomized, controlled pilot trial

Journal: BMJ Open

Manuscript ID bmjopen-2015-008338.R1


Date Submitted by the Author: 23-Aug-2015

Complete List of Authors: Lee, Hye-Yoon; Pusan national university Korean medicine hospital, Internal medicine Nam, Jong-Kil; Pusan National University Yangsan Hospital, Urology

Lee, Sang-Don; Pusan National University Yangsan Hospital, Urology Lee, Dong-Hoon; Pusan National University Yangsan Hospital, Urology Han, Ji-Yeon; Pusan National University Yangsan Hospital, Urology Yoon, Young-Ju; Pusan National University Korean medicine Hospital, Internal medicine Lee, Ji-Hye; Pusan National University Korean medicine Hospital, Internal medicine Park, Hye-lim; Pusan National University Korean medicine Hospital, Internal medicine Park, Seong-Ha; Pusan National University Korean medicine Hospital, Internal medicine Kwon, Jung-Nam; Pusan National University Korean medicine Hospital,

Internal medicine


Urology




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Moxibustion as an adjuvant for benign prostatic hyperplasia with lower urinary tract symptoms: a 1

protocol for a parallel-group, randomized, controlled pilot trial 2

3

4

Hye-Yoon Lee1, 2

, Jong-Kil Nam3, 4

, Sang-Don Lee3, 4

, Dong-Hoon Lee3, 4

, Ji-Yeon Han3, 4

, Young-Ju Yoon1, 5

, Ji-5

Hye Lee1, 6

, Hye-lim Park1, 2

, Seong-Ha Park1, 5


6

7

1Department of Internal Medicine, Pusan National University Korean Medicine Hospital, Yangsan, 626-770, 8

South Korea 9

2Department of Korean Medicine, School of Korean Medicine, Pusan National University, Yangsan, 626-870, 10

South Korea 11

3Department of Urology, Pusan National University Yangsan Hospital, Yangsan, 602-739, South Korea 12

4Department of Urology, School of Medicine, Pusan National University, Yangsan, 626-770, South Korea 13

5Division of Clinical Medicine, School of Korean Medicine, Pusan National University, Yangsan, 626-870, 14

South Korea 15

6Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, 626-16

870, South Korea 17

18

Authors’ email addresses: 19

Hye-Yoon Lee: [email protected] 20

Jong-Kil Nam: [email protected] 21

Sang-Don Lee: [email protected] 22

Dong-Hoon Lee: [email protected] 23

Ji-Yeon Han: [email protected] 24

Young-Ju Yoon: [email protected] 25

Ji-Hye Lee: [email protected] 26

Hye-lim Park: [email protected] 27

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Seong-Ha Park: [email protected] 1

2

*Corresponding author: Jung Nam Kwon, KMD, PhD 3

Address: Department of Korean Medicine, School of Korean Medicine, Pusan National University, 20 Gueno-ro, 4

Mulgeum-eup, Yangsan, 626-770, Gyeongnam, South Korea 5

Telephone: 82-55-360-5666 6

Fax: 82-55-360-5736 7

Email: [email protected] 8

9

10

11

12

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ABSTRACT 1

Introduction 2

This study aims to explore the feasibility of moxibustion as a supplementary intervention and to assess the 3

sample size for verifying the effectiveness and safety of integrative treatment involving moxibustion compared 4

with conventional treatment for patients with benign prostate hyperplasia (BPH) accompanying moderate to 5

severe lower urinary tract symptoms (LUTS). 6

7

Methods and analysis 8

A total of 60 patients diagnosed with benign prostatic hyperplasia by a urologist based on prostate size, prostate-9

specific antigen (PSA), and clinical symptoms will participate of their own free will, and urologists will monitor 10

patients and evaluate their symptoms. The patients will be randomized into a conventional group or integrative 11

group with a 1:1 allocation according to computer-generated random numbers concealed in opaque, sealed, 12

sequentially numbered envelopes. Watchful waiting or oral medication including alpha-blocker, 5-alpha-13

reductase inhibitors (5-ARIs) or anti-muscarinic drugs will be offered as a conventional treatment. Integrative 14

treatment will include moxibustion therapy in addition to the conventional treatment. The moxibustion therapy 15

will be conducted twice per week for four weeks on the bilateral acupoints SP6, LR3 and CV4 by a qualified 16

Korean medical doctor (KMD). The primary outcome will be the international prostate symptom score (IPSS) 17

after 8 sessions. The secondary outcomes will be the post-void residual urine volume (PVR), the maximum 18

urinary flow rate (Qmax), IPSS, the results of a short-form 36-question health survey (SF-36) after 12 weeks 19

and the patients' global impression of changes (PGIC) at each visit. 20

21

Ethics and dissemination 22

Written informed consent will be obtained from all participants. This study was approved by the IRBs of both 23

PNUYH and PNUKH. 24

Trial registration number: clinicaltrials.gov. NCT02051036 (Date: 01/26/2014) 25

26

27 Strengths and limitations of this study 28

29 � The design of this clinical trial is based on an experts’ conference with KMDs, urologic doctors (UDs), 30

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and an Eastern-Western integrative medicine specialist who has both MD and KMD licenses to 1

develop an optimal integrative treatment. 2

� Optimal conventional oral medications and a customized number of moxibustion layers for each 3

patient are used to reflect the real clinical setting. 4

� This study’s results can serve as a basis for further large studies or studies of intractable urinary 5

disorders. 6

� The statistical power of the study may be low due to the small sample size. 7

� Practitioners and patients cannot be blinded. 8

9

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INTRODUCTION 1

2 Korean statistical data show that the prevalence of benign prostatic hyperplasia (BPH) in men over 65 years was 3



2. 4

BPH causes lower urinary tract symptoms (LUTS) by directly disturbing the bladder outlet or increasing the 5

tension and resistance of smooth muscles3. For treatment, watchful waiting at the beginning and behaviour 6


, and these methods have proved effective in improving 7


. 8

However, this conventional treatment is limited by certain side effects. For alpha-blockers, rhinitis (6.6%), 9

dizziness (4.4%)5, abnormal ejaculation (2.1-2.8%)

5 8, and faintness (5.4%)

9 as an indicator of cardiovascular 10

side effects of tamsulosin have been observed. Additionally, abnormal ejaculation (14.2%-28.1%) caused by 11

silodosin8 10

; cardiovascular adverse events (5.7% hypertension, 3.9% non-hypertension)11

and mild dizziness 12

(13.9%)9 caused by alfuzosin; severe dizziness leading to drug-suspension (2.0%) caused by terazosin

12; and 13

erectile dysfunction (3.56%), dizziness (4.41%), postural hypotension (4.03%) and asthenia (4.08%)13

caused by 14

doxazosin have been verified. In addition, erectile dysfunction (4.53%), dizziness (2.33%), postural hypotension 15

(2.56%), decreased libido (2.36%) and abnormal ejaculation (1.78%)13

caused by finasteride and dry mouth 16

(24%), dyspepsia (5%), back pain (5%), micturition disorder (5%), constipation (3%), and urinary retention 17

(3%)14

caused by tolterodine have been shown to occur. In particular, when two or more types of these 18

medications are combined, each side effect is expected; thus, careful use only for patients with moderate to 19

severe BPH is recommended4. 20

To overcome this limitation, many studies investigating complementary and alternative medical (CAM) 21

treatment have been conducted, but the 2011 American Urological Association’s (AUA) guideline reported that 22

no definite evidence exists to recommend CAM treatment due to the lack of quality and quantity of CAM 23

studies of BPH3. 24

In contrast, clinical studies of acupuncture or herbal medication for BPH with LUTS have been consistently 25

performed15-19

and have demonstrated the effectiveness of these methods. Moxibustion has been shown to be 26


, but well-designed clinical trials to prove its effectiveness are lacking. 27

Therefore, we designed a pilot trial to explore the feasibility of moxibustion as an adjuvant for BPH with LUTS 28

based on the effectiveness and safety and to estimate the proper sample size for a future, large comparative 29

effectiveness study, with the purpose of developing an optimal integrative treatment that can be accepted by 30

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both MDs and KMDs in the present medical system. The design of this clinical trial is based on a literature 1

survey and an experts’ conference with KMDs, urologic doctors (UDs), and an Eastern-Western integrative 2

medicine specialist who has both MD and KMD licenses. This pilot study is a randomized controlled trial with a 3

parallel-group, 1:1 allocation, exploratory and pragmatic design. 4

5

6

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METHODS AND ANALYSIS 1

2

1. Aims 3

The present study aims to evaluate the feasibility of moxibustion as an adjuvant for conventional treatment in 4

BPH patients and to assess the proper sample size for verifying, in future studies, the effectiveness and safety of 5

integrative treatment compared with conventional treatment for patients with BPH accompanying LUTS. This is 6

a single-centre, assessor- and analyser-blinded, parallel-group, 1:1 allocation, pragmatic randomized controlled 7

study. 8

9

2. Recruitment 10

Notices were posted in front of the Pusan National University Yangsan Hospital (PNUYH) urologic office and 11

the Pusan National University Korean Medicine Hospital (PNUKH) genitor-urinary clinic office, and 12

advertising for the study was also placed on the internet homepage of PNUKH. A UD will confirm the diagnosis 13

of benign prostatic hyperplasia and needlessness of surgical treatment for patients who volunteer to participate. 14

A KMD will thoroughly examine all inclusion/exclusion criteria and explain the trial to eligible patients. When 15

the patient decides to participate in the study, the KMD will obtain written informed consent, and a baseline 16

assessment will be performed. The progress of the study will consist of a screening phase, a treatment phase and 17

follow-up. A more detailed description of the study is shown in figure 1. The time schedule for participation is 18

shown in table 1. 19

20

3. Study design 21

Randomization and allocation concealment 22

A statistician who does not take part in this study will place the computer-generated random list into each 23

double-layered opaque envelope, seal it and write the numbers in sequence. A practitioner will give the envelope 24

to the patient according to the visit order and open it with the patient. 25

26

4. Patients 27

4.1. Sample size 28

The sample size calculation was not performed based on a power calculation because this is a pilot study. The 29

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sample size was determined based on estimates of the number of patients expected to participate and the 1

minimum number to evaluate the pragmatic purpose of this trial. Thus, a sample size of 30 per group and total 2

number of 60 will be included, which is larger than the minimum number required for pilot studies21

. 3

4

4.2. Inclusion criteria 5

1. Male patients aged 20-80 years diagnosed with BPH with a prostate size over 20 gm 6

2. IPSS score ≥ eight 7

3. Written informed consent obtained 8

4. Patient must understand and answer the IPSS 9

10

4.3. Exclusion criteria 11

1. Prostate or bladder malignancy 12

2. Received herbal medication for lower urinary tract symptoms within one week 13

3. History of a brain disease that can cause urinary difficulty 14

4. Difficulty answering IPSS due to cognitive impairment 15

5. Signs of acute urinary tract infection 16

6. Diabetic mellitus 17

7. Neurogenic bladder 18

19

4.4. Drop-out criteria and process of management 20

4.4.1. Definition of drop-out 21

Completed cases will be defined as patients who finish the treatment progress and follow-up. Patients who 22

cannot complete the study due to side effects or for other reasons will be considered drop-out cases. 23

24

4.4.2. Drop-out criteria 25

The researcher may stop treatment and observation of a patient according to prescribed criteria, and the patient 26

can drop-out voluntarily at any time. The drop-out criteria are as follows. 27

1. Violation of inclusion/exclusion criteria 28

2. Serious adverse events or adverse events making a patient wish to drop out 29

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3. Severe systemic disease that was not recognized at baseline 1

4. Patients or a legal representative demand cessation of the trial due to unsatisfying effects or withdrawal of 2

consent 3

5. Trial compliance of less than 80%; should attend at least 7 of 8 treatment sessions in the integrative group 4

and all of three major assessments (baseline, visit 9 and visit 10) in both groups 5

6. Protocol violation of patient or researcher 6

7. Difficulty conducting moxibustion due to newly developed disease or uncooperative manner 7

8. Patients not replying to outcome measures 8

9. Patient’s desire or UD’s recommendation for surgical treatment (including minimally invasive therapies) 9

10

4.4.3. Management process 11

The drop-out date, time and reason will be recorded on the end report. Patients can drop out voluntarily for any 12

reason, at any time, and are not required to submit a reason. The researcher should make every effort to follow 13

up with patients who have dropped out and record the reason for drop-out or the reason for not being able to 14

determine a drop-out cause. 15

16

5. Blinding 17

5.1. Blinding of outcome assessors and data analysers 18

The practitioner and patients cannot be blinded because this is an open-label study for moxibustion treatment. 19

Assessors and analysers will be blinded. Urodynamic testing will be performed by an assistant who does not 20

take part in the trial, and participants will be asked not to reveal their allotted group to the assistant. Subjective 21

outcomes will be recorded by the patient. The groups will be marked “A” and “B” when the data are sent to the 22

statistician to ensure that the groups are not recognized as the control group and experimental group. Un-23

blinding of the assessors will be permissible only in the case of a serious adverse event. 24

25

5.2. The rationale for the lack of a sham moxibustion group 26

For the pragmatic purpose of the future study, we decided to reflect the real clinical situation without omitting 27

the patients’ additional time, effort and expectations by comparing patients who receive conventional treatment 28

with patients who receive both conventional treatment and complementary treatment. A sham or placebo 29

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intervention group is the ideal method for efficacy studies with an optimal, strictly restricted design to minimize 1

all influencing factors to prove the efficacy of a specific component of intervention22 23

. Consequently, a sham 2

moxibustion group will not be included in this study. 3

4

6. Interventions 5

6.1. Conventional treatment protocol 6

The conventional treatment will be set as the optimum treatment for each patient to develop a reasonable 7


. 8

The optimum treatment for each patient will be based on the UD’s opinion. The UD will discuss behavioural 9

modifications, such as water intake, with the patient. Watchful waiting will be used for patients without renal 10

insufficiency, urinary retention, recurring infection or complications of bladder-outlet obstruction (BOO). Oral 11

medications will be prescribed when no therapeutic effect is observed after watchful waiting, and the 12

medications will be selected in consideration of overactive bladder, prostate size and prostate-specific antigen 13

(PSA). Preferentially, an alpha-blocker, such as alfuzosin, doxazosin, tamsulosin or terazosin, will be used for 14

functional symptom mitigation. 5-ARIs, such as dutasteride and finasteride, will be used when the prostatic 15

volume is > 40 ml or PSA > 1.4 ng/ml. For cases of a high risk of BPH progression, prostate ≥ 30 mg or PSA ≥ 16

1.5 ng/ml, a combination of an alpha-blocker and a 5-ARI will be used. Anticholinergic agents, such as 17

tolterodine, will be prescribed for patients with overactive bladder but will need to be monitored for patients 18

with ≥ 250 ml post-void residual urine. The conventional treatment components can be changed at the discretion 19

of the UD because this research is a pragmatic study to evaluate the effectiveness and safety of additional 20

moxibustion therapy and the conventional treatment will still be maintained for the last follow-up3 4

. 21

22

6.2. Integrative treatment protocol 23

Moxibustion therapy will be added to the conventional treatment described in section 6.1 twice per week for 24

four weeks. The moxibustion therapy will be conducted by a skilled KMD who has at least two years’ 25

experience in the clinic. The timeframes of the conventional treatment group (CG) and the integrative treatment 26

group (IG) are shown in figure 2. Both the apparatus type and mini-pillar type moxibustion will be used. 27

The apparatus types are a Hatnim-moxa apparatus (Bosungsa, Incheon, South Korea) and a moxa pillar 28

(Bosungsa, South Korea) that generates 65-70 °C of heat. Moxibustion will be conducted at acupoints CV4 on 29

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and 1


26

. Additional gauze will be offered layer by layer when the patient requests it due to 2

intolerable heat. This apparatus-moxibustion will be stopped if the patient complains of intolerable heat even 3

after the additional gauze is offered more than three times. If the patient cannot feel any heat once the moxa 4

pillar is totally burned, the apparatus-moxibustion will be conducted one more time; the procedure can be 5

performed one more time as before, but the number of apparatus-moxibustion applications cannot exceed three. 6

The therapy can be stopped if a second-degree or higher burn occurs even before completing eight treatment 7

sessions. 8

Kanghwa mini-moxa of “lowest” intensity, which generates heat of approximately 45 °C, will be used for mini-9


and LR320 28 29

10

(figure 4). The mini-moxa will be removed when totally burned, which takes approximately 5 minutes, but it 11

may be removed if the patient complains of intolerable heat. The mini-moxa will not be repeated on the acupoint 12

on which moxibustion was stopped per the patient’s request. Repetitive mini-moxa will be performed on the 13

acupoints at which the patient did not feel heat and completed prior mini-moxa for the entire burning period, up 14

to a maximum of seven times on each point. Beginning with the second session, the treated region will be 15

checked and further mini-moxa will not be allowed on an acupoint where a second-degree or higher burn 16

occurred. In this case, the mini-moxa will be re-started after the burn is completely healed. 17


, Liu QG31

18

and Wang Y26

, who reported the effective results and clinical experiences of two KMDs considering practicality 19

in terms of the patients’ general social environment and the accessibility of the hospital. The number of 20

performed moxibustion treatments will be recorded in both the electronic medical record (EMR) and case report 21

form (CRF) at every visit in adherence with intervention protocols. 22


, 23

and in this case, the patient will not be considered a study drop-out. However, if a patient cannot continue the 24

treatment because of discomfort from the moxibustion smoke, allergic response or pigmentation from the moxa-25

soot, he cannot be regarded as having completed the trial. 26

27

6.3. Prohibited or allowed parallel medical treatments 28

Flexible oral medications according to the discretion of the UD's opinion are allowed to offer the best treatment 29

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for each patient; thus, the medications will not be fixed without variation. All types of medication therapy based 1

on AUA guidelines and the Korean prostate society guideline will be allowed. 2

Surgical treatment, including transurethral resection of the prostate (TURP), transurethral incision of the 3

prostate (TUIP), abdominal prostatectomy, minimally invasive therapy using a laser, transurethral needle 4

ablation of the prostate (TUNA), and transurethral microwave thermotherapy (TUMT), are prohibited; therefore, 5

patients who want or are recommended for such therapies cannot participate in this trial. 6

7

6.4. Treatment of adverse events 8

We will disinfect and dress the wound when a second-degree or higher burn occurs and will refer the patient to 9

dermatology to receive proper treatment when a third-degree or higher burn occurs. 10

11

7. Outcome measures 12

This study aims to 1) obtain information on whether moxibustion can be beneficial to BPH patients 13

accompanying LUTS as an adjuvant treatment based on its effectiveness and safety and 2) determine the effect 14

size to calculate the proper sample size for future research. Thus, outcomes regarding the functional 15

improvement and the adverse events will be measured. 16

17

7.1 Primary outcome measure 18

The IPSS after 8 sessions will be the primary outcome measure. IPSS was developed by the AUA in 1992, and a 19

question regarding quality of life (QoL) was later added33


. IPSS 20

consists of seven sub-themes of incomplete emptying, frequency, intermittency, urgency, weak stream, straining 21

and nocturia. The severity scoring is as follows: 0-7, mildly symptomatic; 8-19, moderately symptomatic; and 22

20-35, severely symptomatic BPH. The separate QoL question requires the respondent to select a QoL category 23

ranging from zero (delighted) to six (terrible). 24

25

7.2 Secondary outcome measure 26

7.2.1. Patient’s global impression of changes (PGIC) 27

The PGIC will be recorded for each patient at every visit after the first treatment. PGIC is a scoring system used 28

to evaluate the level of change from the beginning of the treatment, either conventional or integrative, to the 29

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time of the PGIC check. This scale considers limitations of physical activity, symptoms, emotions and QoL in 1

general. The scoring is as follows: no change (or condition has become worse), 1; almost the same, hardly any 2

change at all, 2; slightly better, but no noticeable change, 3; somewhat better, but the change has not made any 3

real difference, 4; moderately better and a slight but noticeable change, 5; better and a definite improvement that 4

has made a real and worthwhile difference, 6; a great deal better and a considerable improvement that has made 5

a substantial difference, 7. In a similar way, each patient will be asked to circle one of the numbers 0 (much 6

better) to 10 (much worse) written on a straight line that represents the change from the beginning to the time of 7

evaluation35

. 8

9

7.2.2. The short-form 36-question health survey (SF-36) 10

The SF-36 will be checked at the baseline, after 4 sessions, after 8 sessions and after 12 weeks from the baseline. 11

The SF-36 is a commonly used scale to evaluate health-related quality of life (HRQOL). This scale consists of 12

physical function, physical role capability, bodily pain, general health perceptions, vitality, social role capability, 13


. 14

15

7.2.3. The maximum urinary flow rate (Qmax) 16

Qmax changes from baseline to 12 weeks will be used as an objective outcome measure. Urodynamic study is 17

an invasive method to obtain objective and quantitative data on bladder-outlet function and storage function. 18

Patients will attend the study when they feel a “normal” desire to urinate. The velocity of the external urine 19

stream will be automatically obtained by a calculation using the voided volume and time37

. 20

21

7.2.4. Post-void residual urine volume (PVR) 22

PVR changes from baseline to 12 weeks will be evaluated because PVR increases when bladder-outlet function 23

is incomplete37

. PVR will be checked by ultrasonography immediately after the urodynamic study. 24

25

7.2.5. Persistency on IPSS 26

The IPSS will be checked 12 weeks after the beginning of the study, after 8 weeks of completed moxibustion 27

therapy, to evaluate the persistency of the effects of moxibustion therapy. This period of 12 weeks was 28

determined based on a previous study26, the clinical experiences of two KMDs, and the optimum follow-up 29

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period recommended in conventional treatment guidelines38-40

. 1

2

7.3 Adverse events 3

At every visit, patients will be asked if adverse effects have developed and, if so, what types of adverse effects. 4

In particular, second-degree or higher burns and allergic responses of the skin or whole body will be examined 5

thoroughly, and other types of discomfort will be checked. 6

7

8. Data collection 8

Subjective outcome measurements will be checked for each patient, and objective outcome measurement data 9

will be preserved in both their original form and as an EMR. These data will be written on the CRF by a 10

certificated clinical research coordinator (CRC). To promote patient retention and completion of follow-up, an 11

honorarium will be provided with a differential rate according to the patients' participation. 12

13

9. Statistical analysis 14

9.1. Analysis of efficacy 15

Both intention-to-treat (ITT) and per-protocol (PP) analyses will be performed. The last observation carried 16

forward (LOCF) method will be used for missing data in ITT analysis. The paired t-test will be used for 17

intragroup before/after treatment comparisons. The independent t-test will be used for intergroup comparisons. 18

For non-parametric data, the Wilcoxon signed-rank test for intragroup and the Wilcoxon rank-sum test for 19

intergroup test will be used. Categorical data, such as adverse effects, will be investigated by calculating the 20

occurrence rate of adverse events for each group and then performing analysis with the chi-square test or 21

Fisher’s exact test. If statistically significant differences between two groups are observed or covariance is 22

expected, analysis of covariance (ANCOVA) will be used. All of the statistical analysis will be done with two-23

tailed tests, and the significance level will be set as 0.05. 24

25

10. Safety 26

Expected adverse events, such as burns and allergic responses, will be recorded along with their modality, date 27

of occurrence, and duration. Patients will report other unexpected adverse events freely. The severity of the 28

adverse events will be categorized according to the WHO 5-grade performance status classification as follows: 0, 29

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able to carry out all normal activity without restriction; 1, restricted in strenuous activity but ambulatory and 1

able to carry out light work; 2, ambulatory and capable of all self-care but unable to carry out any work 2

activities and up and about more than 50% of waking hours; 3, symptomatic and in a chair or in bed for greater 3

than 50% of the day but not bedridden; 4, completely disabled, unable to carry out any self-care; totally 4

confined to bed or chair. The cause-and-effect relation between the intervention and adverse events will be 5

assessed according to the WHO-Uppsala Monitoring Centre (UMC) causality categories of 1, certain; 2, 6

probable/likely; 3, possible; 4, unlikely; 5, conditional/unclassified; 6, unassessable/unclassifiable. 7

To minimize the expected adverse events, we will describe the risk of adverse events to patients who have prior 8

allergic responses to moxibustion therapy, allergic rhinitis or allergic conjunctivitis. Patients will be informed to 9

notify the practitioner if they experience such symptoms during the treatment to receive proper and prompt 10

treatment. The treatment will be performed in a well-ventilated room, and a mask will be offered to cover the 11

patient’s mouth and nose. To prevent burns, patients will be educated about indirect moxibustion therapy and its 12

precautions and informed to notify the practitioner promptly if they feel intolerable heat and wish to stop the 13

treatment. The principal investigator (PI) will describe and assess all of the symptoms that occur during the 14

clinical trial and will report to the institutional review board (IRB) to determine whether to continue or stop the 15

study when serious adverse events occur. 16

Patients who suffer from adverse events will be treated as described in section 6.4. Additionally, patients who 17

suffer harm from this trial participation will be cared for through insurance. All patients will be informed of and 18

sign off on the “regulation concerning subject compensation”, including detailed descriptions of this regulation. 19

20

11. Monitoring 21

The independent data monitoring committee (DMC), composed of one KMD and one clinical research expert, 22

will examine the process of progress and whether the trial follows the study plan, the standard guidelines, and 23

clinical-trials management criteria and other related standards. Monitoring will be conducted by regular visits 24

and phone calls. The DMC will check the original record and case report forms. If any problem is found, the 25

DMC will discuss this with the PI. If any serious problems that could threaten the security of patients are found, 26

the DMC will discuss this with the IRB and PI. The PI will make the final decision as to whether to continue or 27

to terminate the trial, and the IRB can order the PI to terminate the trial in the case of a serious problem. 28

29

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12. Ethical considerations and dissemination 1

12.1. Written informed consent and study approval 2

This study was approved by the IRBs of both PNUYH and PNUKH. A signed informed consent will be 3

submitted from each patient to the practitioner. If any changes to the inclusion/exclusion criteria, outcome 4

measure methods or data analysis are demanded, the decision will be made through a discussion between the 5

UD and KMD. The changed contents would need to be reapproved by the IRB and reflected in the patient-6

explanation and study registration (clinicaltrials.gov), and a new consent from the patient would need to be 7

obtained. 8

9

12.2. Private information protection 10

Collected data from patients will be safeguarded with specific serial numbers without any personally identifiable 11

information so that nobody can recognize the patients except a security manager who has a code-table. 12

Computer-stored personal information will be secured using a password, and all matters related to security will 13

be supervised by the PI. Publication will not include any personally identifiable information, and data will be 14

treated anonymously. Strict security is assured even in a case of a patient dropping out mid-study and after the 15

end of the study. 16

Data used for the study will be disposed of after the collection of materials for a research paper. Computer 17

storage files will be deleted and documents will be shredded on 31st November, 2017. 18

The PI, a monitor and an inspector can read the patients’ records for the purpose of monitoring and progress 19

oversight in terms of laws and ethics. These data will be stored securely in the National Clinical Research 20

Center for Korean Medicine. This matter will be explained to patients, who will also be provided a written 21

explanation. 22

23

12.3. Dissemination 24

The trial results will be disseminated through open-access journals and conferences. 25

26

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DISCUSSION 1

2 This study is the first protocol of a randomized controlled pilot trial in Korea to evaluate the feasibility of 3

moxibustion as an adjuvant to conventional therapy in BPH accompanying LUTS by exploring its effectiveness 4

and safety. 5

The medical system of South Korea has been maintained as a dualized system since the revival of KMD by the 6

enactment of the National Medical Insurance Act in 1951. This system has had some negative aspects, such as 7

the incautious use of medicine combinations and distrust between the two medical fields; however, it has had 8


. Therefore, 9

the necessity of integrative medicine has been propounded steadily to establish a new medical system combining 10


. 11

This study was designed as an investigation of add-on treatment without a placebo control because methods of 12

additional alternative treatments in conjunction with the conventional treatment are considered appropriate in 13


. Despite relatively acceptable rates of adverse 14

events, increased side effects caused by the combination of different types of oral drug4 and by patient 15

vulnerability factors, such as ageing and underlying disease, still must be investigated. Therefore, the 16

effectiveness and safety of adjuvant treatments should be evaluated, after which the adjuvant treatment may be 17

considered for intractable urinary disorders including interstitial cystitis and chronic prostatitis. Additionally, a 18


. Thus, we set 19

broad inclusion/exclusion criteria and flexible interventions allowing for different treatment regimes according 20

to each patient’s medical condition. In addition, conventional oral medication is not restricted to one type 21

considering the pragmatic purpose and the study ethics. The moxibustion therapy has the limitation of 22

inconvenience because patients must visit the hospital for every treatment, while the conventional oral 23

medication can be provided once for a relatively long period; thus, the experts discussed and decided to perform 24

a relatively short-period treatment and to follow up after 12 weeks, as in conventional treatment38

25

This study has some limitations. The 12-week follow-up was set according to the routine check period of 26

conventional treatment but was not sufficient to evaluate the long-term effects. Furthermore, the development of 27

changes cannot be investigated because frequent and regular IPSS checks were not planned in this trial. 28

Therefore, future trials should include more frequent and regular outcome assessments in both groups and a 29

longer follow-up period of at least one year in order to investigate the development of changes in each group 30

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and the persisting effect so that the treatment sessions, period and interval can be properly modified for the final 1

integrative treatment guideline. Another limitation is that the prostate size is not included as an outcome 2

measurement because the feasibility is the main focus rather than definitive assessment of effectiveness. 3

Therefore, studies evaluating the effect of the combined treatment on prostate size should be conducted after the 4

LUTS-reduction effect is demonstrated. Future power analysis studies should be performed by determining the 5

effect size based on the results of this study, and cost-effectiveness studies should be performed to provide 6

important details for decision-makers. 7

8

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TRIAL STATUS 1

2 This study is currently in the recruiting phase. The first patient was enrolled on March 10, 2014, data collection 3

will be complete in approximately December 2015, and the article including results is expected in 4

approximately 2016. 5

6

7

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Acknowledgements 1

This study was supported by the Korea Institute of Oriental Medicine (K14273). 2

3

Contact name: Dal-Seok Oh, Senior Research Fellow 4

Address: 1672 Yuseong-daero, Yuseong-gu, Daejeon 305-811, Korea 5

TEL: +82-42-861-1994 6

E-mail: [email protected] 7

8

Contributors 9

JNK, SDL and JGN conceived the study. JNK, SDL, JKN, JYH, YJY and HYL initiated the study design, and 10

DHL, SHP, JHL and HLP helped with its implementation. JKN, DHL, JHY and HYL performed the intervention 11

and discussed the optimal complementary medicine. HYL drafted the study protocol manuscript. All authors 12

contributed to the refinement of the study protocol and approved the final manuscript. 13

14

Competing interests 15

None 16

17

Access to data 18

The data from this trial will be accessible by contacting the corresponding author. 19

20

Ethics approval 21

The study was approved by IRBs of both Pusan National University Korean Medicine Hospital (IRB approval 22

number 2013021) and Pusan National University Yangsan Hospital (IRB approval number 03-2013-013). 23

24

25

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APPENDIX 1

Table 1. Trial progress 2 3 Period Screening Active treatment F/U

Visit Screening 1 2 3 4 5 6 7 8 9* 10

Week 0 1 2 3 4 12

Consent ●


Medical history ● ○ ○ ○ ○ ○ ○ ○ ○ ● ●

Vital signs ● ○ ○ ○ ○ ○ ○ ○ ○ ●


Conformity

assessment

●

Check PSA ●

Check prostate size

(TRUS)

●

Inclusion/exclusion

criteria

●


visit schedule

● ○ ○ ○ ○ ○ ○ ○ ○ ○

Randomization ●


IPSS ● ○ ● ●

SF-36 ● ○ ● ●

PGIC ○ ○ ○ ○ ○ ○ ○ ● ●

Qmax ● ●

PVR ● ●

FVC ● ●

Adverse event

monitoring

○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Final compliance

assessment

●







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Table 2. International prostate symptom score 1

2

Not

at a

ll

Les

s th

an

1 t

ime

in 5

Les

s th

an

hal

f th

e ti

me

Ab

out

hal

f th

e ti

me

Mo

re t

han

hal

f th

e ti

me

Alm

ost

alw

ays

Incomplete emptying



urinating?

0 1 2 3 4 5

Frequency



0 1 2 3 4 5

Intermittency



0 1 2 3 4 5

Urgency


postpone urination?

0 1 2 3 4 5

Weak stream


urinary stream?

0 1 2 3 4 5

Nocturia

No

ne

1 t

ime

2 t

imes

3 t

imes

4 t

imes

5 t

imes

or

mo

re




0 1 2 3 4 5


Del

ighte

d

Ple

ased

Most

ly

sati

sfie

d

Mix

ed –

ab

ou

t

equ

ally

Most

ly

dis

sati

sfie

d

Un

hap

py

Ter

rib

le



feel about that?

0 1 2 3 4 5 6

Total score: 0-7, mildly symptomatic; 8-19, moderately symptomatic; 20-35, severely symptomatic. 3

4

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Figures 1 2 Figure 1. Trial flowchart 3 4

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1 Figure 2. Timeframe of the integrative treatment group (IG) and conventional treatment group (TG). 2 3

4 5

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Figure 3. Apparatus-type moxibustion on CV4 1

2

3

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Figure 4. Mini-pillar-type moxibustion on bilateral SP6 and LR3 1 2

3

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number

NCT02051036


Registry

01/26/2014.



Support












Studied






Inclusion criteria:






Exclusion criteria:














1 2

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Application for participation

Confirm diagnosis of BPH (PSA, TRUS, IPSS)

Examination by a

urologist

Exclusion: unconfirmed BPH, IPSS<8

Examination by KMD

Full eligibility screening and written informed consent

Confirm enrolment and baseline assessment

Group allocation Allocation

Follow-up

Outcome assessment at 4

Outcome assessment at 12 weeks

Analysis Analysis

Treatment Integrative group (n=30)

conventional treatment, moxibustion

Conventional group (n=30)

conventional treatment

Exclusion: neurogenic bladder, acute urinary tract

infection, recommended surgical treatment

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1










Roles and

responsibilities






______23______




______23______

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2

Introduction

Background and

rationale



______5_______





______6_______




______7_______



______8_______


administered

______10______



______10,11____



______11______

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial ______11______





______12______



______7______

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3



______7______



Allocation:

Sequence

generation





______7__ ____

Allocation

concealment

mechanism



_______7______


interventions

_______7______



_______9______



_______9______


Data collection

methods





_____13- 15_____



_______14______

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4




______16_____



______14______




______14______

Methods: Monitoring




needed

______15______



______15______



______14______



_____14,15_____


Research ethics

approval


Protocol

amendments



regulators)

______15______

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5


how (see Item 32)

______16______



_____none_____



______16______

Declaration of

interests




______23______

Ancillary and post-

trial care


participation

______15______




______16______



Appendices

Informed consent

materials


Biological

specimens



___ __




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Moxibustion as an adjuvant for benign prostatic hyperplasia with lower urinary tract symptoms: a protocol for a parallel-

group, randomized, controlled pilot trial

Journal: BMJ Open

Manuscript ID bmjopen-2015-008338.R2


Date Submitted by the Author: 15-Sep-2015

Complete List of Authors: Lee, Hye-Yoon; Pusan national university Korean medicine hospital, Internal medicine Nam, Jong-Kil; Pusan National University Yangsan Hospital, Urology

Lee, Sang-Don; Pusan National University Yangsan Hospital, Urology Lee, Dong-Hoon; Pusan National University Yangsan Hospital, Urology Han, Ji-Yeon; Pusan National University Yangsan Hospital, Urology Yoon, Young-Ju; Pusan National University Korean medicine Hospital, Internal medicine Lee, Ji-Hye; Pusan National University Korean medicine Hospital, Internal medicine Park, Hye-lim; Pusan National University Korean medicine Hospital, Internal medicine Park, Seong-Ha; Pusan National University Korean medicine Hospital, Internal medicine Kwon, Jung-Nam; Pusan National University Korean medicine Hospital,

Internal medicine


Urology




BMJ Open on A


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1

Moxibustion as an adjuvant for benign prostatic hyperplasia with lower urinary tract symptoms: a 1

protocol for a parallel-group, randomized, controlled pilot trial 2

3

4

Hye-Yoon Lee1, 2

, Jong-Kil Nam3, 4

, Sang-Don Lee3, 4

, Dong-Hoon Lee3, 4

, Ji-Yeon Han3, 4

, Young-Ju Yun1, 5

, Ji-5

Hye Lee1, 6

, Hye-lim Park1, 2

, Seong-Ha Park1, 5


6

7

1Department of Internal Medicine, Pusan National University Korean Medicine Hospital, Yangsan, 626-770, 8

South Korea 9

2Department of Korean Medicine, School of Korean Medicine, Pusan National University, Yangsan, 626-870, 10

South Korea 11

3Department of Urology, Pusan National University Yangsan Hospital, Yangsan, 602-739, South Korea 12

4Department of Urology, School of Medicine, Pusan National University, Yangsan, 626-770, South Korea 13

5Division of Clinical Medicine, School of Korean Medicine, Pusan National University, Yangsan, 626-870, 14

South Korea 15

6Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, 626-16

870, South Korea 17

18

Authors’ email addresses: 19

Hye-Yoon Lee: [email protected] 20

Jong-Kil Nam: [email protected] 21

Sang-Don Lee: [email protected] 22

Dong-Hoon Lee: [email protected] 23

Ji-Yeon Han: [email protected] 24

Young-Ju Yun: [email protected] 25

Ji-Hye Lee: [email protected] 26

Hye-lim Park: [email protected] 27

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2

Seong-Ha Park: [email protected] 1

2

*Corresponding author: Jung Nam Kwon, KMD, PhD 3

Address: Department of Korean Medicine, School of Korean Medicine, Pusan National University, 20 Guemo-4

ro, Mulgeum-eup, Yangsan, 626-770, Gyeongnam, South Korea 5

Telephone: 82-55-360-5666 6

Fax: 82-55-360-5736 7

Email: [email protected] 8

9

10

11

12

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ABSTRACT 1

Introduction 2

This study aims to explore the feasibility of moxibustion as a supplementary intervention and to assess the 3

sample size for verifying the effectiveness and safety of integrative treatment involving moxibustion compared 4

with conventional treatment for patients with benign prostate hyperplasia (BPH) accompanying moderate to 5

severe lower urinary tract symptoms (LUTS). 6

7

Methods and analysis 8

A total of 60 patients diagnosed with benign prostatic hyperplasia by a urologist based on prostate size, prostate-9

specific antigen (PSA), and clinical symptoms will participate of their own free will, and urologists will monitor 10

patients and evaluate their symptoms. The patients will be randomized into a conventional group or integrative 11

group with a 1:1 allocation according to computer-generated random numbers concealed in opaque, sealed, 12

sequentially numbered envelopes. Watchful waiting or oral medication including alpha-blocker, 5-alpha-13

reductase inhibitors (5-ARIs) or anti-muscarinic drugs will be offered as a conventional treatment. Integrative 14

treatment will include moxibustion therapy in addition to the conventional treatment. The moxibustion therapy 15

will be conducted twice per week for four weeks on the bilateral acupoints SP6, LR3 and CV4 by a qualified 16

Korean medical doctor (KMD). The primary outcome will be the international prostate symptom score (IPSS) 17

after 8 sessions. The secondary outcomes will be the post-void residual urine volume (PVR), the maximum 18

urinary flow rate (Qmax), IPSS, the results of a short-form 36-question health survey (SF-36) after 12 weeks 19

and the patients' global impression of changes (PGIC) at each visit. 20

21

Ethics and dissemination 22

Written informed consent will be obtained from all participants. This study was approved by the IRBs of both 23

PNUYH and PNUKH. The trial results will be disseminated through open-access journals and 24

Trial registration number: clinicaltrials.gov. NCT02051036 (Date: 01/26/2014) 25

26

27 Strengths and limitations of this study 28

29 � The design of this clinical trial is based on an experts’ conference with KMDs, urologic doctors (UDs), 30

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and an Eastern-Western integrative medicine specialist who has both MD and KMD licenses to 1

develop an optimal integrative treatment. 2

� Optimal conventional oral medications and a customized number of moxibustion layers for each 3

patient are used to reflect the real clinical setting. 4

� This study’s results can serve as a basis for further large studies or studies of intractable urinary 5

disorders. 6

� The statistical power of the study may be low due to the small sample size. 7

� Practitioners and patients will not be blinded. 8

9

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5

INTRODUCTION 1

2 Korean statistical data show that the prevalence of benign prostatic hyperplasia (BPH) in men over 65 years was 3



2. 4

BPH causes lower urinary tract symptoms (LUTS) by directly disturbing the bladder outlet or increasing the 5

tension and resistance of smooth muscles3. For treatment, watchful waiting at the beginning and behaviour 6


, and these methods have proved effective in improving 7


. 8

However, this conventional treatment is limited by certain side effects. For alpha-blockers, rhinitis (6.6%), 9

dizziness (4.4%) and abnormal ejaculation (2.8%)5 caused by tamsulosin have been observed. Moreover, 10

abnormal ejaculation (14.2%-28.1%) caused by silodosin8 9; cardiovascular adverse events (5.7% hypertension, 11

3.9% non-hypertension)10

and mild dizziness (13.9%)11

caused by alfuzosin; severe dizziness leading to drug-12

suspension (2.0%) caused by terazosin12

; and dizziness (4.41%), postural hypotension (4.03%) and asthenia 13

(4.08%)13

caused by doxazosin have been verified. In addition, erectile dysfunction (4.53%), decreased libido 14

(2.36%) and abnormal ejaculation (1.78%)13

caused by finasteride have been identified; and dry mouth (24%), 15

dyspepsia (5%), back pain (5%) and micturition disorder (5%)14

caused by tolterodine have been shown to occur. 16

In particular, when two or more types of these medications are combined, each side effect is expected; thus, 17

careful use only for patients with moderate to severe BPH is recommended4. 18

To overcome this limitation, many studies investigating complementary and alternative medical (CAM) 19

treatment have been conducted, but the 2011 American Urological Association’s (AUA) guideline reported that 20

no definite evidence exists to recommend CAM treatment due to the lack of quality and quantity of CAM 21

studies of BPH3. 22

In contrast, clinical studies of acupuncture or herbal medication for BPH with LUTS have been consistently 23

performed15-19

and have demonstrated the effectiveness of these methods. Moxibustion has been shown to be 24


, but well-designed clinical trials to prove its effectiveness are lacking. 25

Therefore, we designed a pilot trial to explore the feasibility of moxibustion as an adjuvant for BPH with LUTS 26

based on the effectiveness and safety and to estimate the proper sample size for a future, large comparative 27

effectiveness study, with the purpose of developing an optimal integrative treatment that can be accepted by 28

both MDs and KMDs in the present medical system. The design of this clinical trial is based on a literature 29

survey and an experts’ conference with KMDs, urologic doctors (UDs), and an Eastern-Western integrative 30

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medicine specialist who has both MD and KMD licenses. This pilot study is a randomized controlled trial with a 1

parallel-group, 1:1 allocation, exploratory and pragmatic design. 2

3

4

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METHODS AND ANALYSIS 1

2

1. Aims 3

The present study aims to evaluate the feasibility of moxibustion as an adjuvant for conventional treatment in 4

BPH patients and to assess the proper sample size for verifying, in future studies, the effectiveness and safety of 5

integrative treatment compared with conventional treatment for patients with BPH accompanying LUTS. This is 6

a single-centre, assessor- and analyser-blinded, parallel-group, 1:1 allocation, pragmatic randomized controlled 7

study. 8

9

2. Recruitment 10

Notices were posted in front of the Pusan National University Yangsan Hospital (PNUYH) urologic office and 11

the Pusan National University Korean Medicine Hospital (PNUKH) genito-urinary clinic office, and advertising 12

for the study was also placed on the internet homepage of PNUKH. A UD will confirm the diagnosis of benign 13

prostatic hyperplasia and needlessness of surgical treatment for patients who volunteer to participate. A KMD 14

will thoroughly examine all inclusion/exclusion criteria and explain the trial to eligible patients. When the 15

patient decides to participate in the study, the KMD will obtain written informed consent, and a baseline 16

assessment will be performed. The progress of the study will consist of a screening phase, a treatment phase and 17

follow-up. A more detailed description of the study is shown in figure 1. The time schedule for participation is 18

shown in table 1. 19

20

3. Study design 21

Randomization and allocation concealment 22

Within 14 days from recruitment, each patient will be allotted to the conventional or integrative group according 23

to the concealed random list. A statistician who does not take part in this study will place the computer-24

generated random list into each double-layered opaque envelope, seal it and write the numbers in sequence. The 25

KMD will give the envelope to the patient according to the visit order and open it with the patient. 26

27

4. Patients 28

4.1. Sample size 29

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The sample size calculation was not performed based on a power calculation because this is a pilot study. The 1

sample size was determined based on estimates of the number of patients expected to participate and the 2

minimum number to evaluate the pragmatic purpose of this trial. Thus, a sample size of 30 per group and total 3

number of 60 will be included, which is larger than the minimum number recommended for pilot studies21

. 4

5

4.2. Inclusion criteria 6

1. Male patients aged 20-80 years diagnosed with BPH with a prostate size over 20 gm 7

2. International prostate symptom score (IPSS) ≥ eight 8

3. Written informed consent obtained 9

4. Patient must understand and answer the IPSS 10

11

4.3. Exclusion criteria 12

1. Prostate or bladder malignancy 13

2. Received herbal medication for lower urinary tract symptoms within one week 14

3. History of a brain disease that can cause urinary difficulty 15

4. Difficulty answering IPSS due to cognitive impairment 16

5. Signs of acute urinary tract infection 17

6. Diabetic mellitus 18

7. Neurogenic bladder 19

20

4.4. Drop-out criteria and process of management 21

4.4.1. Definition of drop-out 22

Completed cases will be defined as patients who finish the treatment progress and follow-up. Patients who 23

cannot complete the study due to side effects or for other reasons will be considered drop-out cases. 24

25

4.4.2. Drop-out criteria 26

The researcher may stop treatment and observation of a patient according to prescribed criteria, and the patient 27

can drop-out voluntarily at any time. The drop-out criteria are as follows. 28

1. Violation of inclusion/exclusion criteria 29

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2. Serious adverse events or adverse events making a patient wish to drop out 1

3. Severe systemic disease that was not recognized at baseline 2

4. Patients or a legal representative demand cessation of the trial due to unsatisfying effects or withdrawal of 3

consent 4

5. Trial compliance of less than 80%; should attend at least 7 of 8 treatment sessions in the integrative group 5

and all of three major assessments (baseline, visit 9 and visit 10) in both groups 6

6. Protocol violation of patient or researcher 7

7. Difficulty conducting moxibustion due to newly developed disease or uncooperative manner 8

8. Patients not replying to outcome measures 9

9. Patient’s desire or UD’s recommendation for surgical treatment (including minimally invasive therapies) 10

11

4.4.3. Management process 12

The drop-out date, time and reason will be recorded on the end report. Patients can drop out voluntarily for any 13

reason, at any time, and are not required to submit a reason. The researcher should make every effort to follow 14

up with patients who have dropped out and record the reason for drop-out or the reason for not being able to 15

determine a drop-out cause. 16

17

5. Blinding 18

5.1. Blinding of outcome assessors and data analysers 19

The practitioner and patients cannot be blinded because this is an open-label study for moxibustion treatment. 20

Assessors and analysers will be blinded. Urodynamic testing will be performed by an assistant who does not 21

take part in the trial, and participants will be asked not to reveal their allotted group to the assistant. Subjective 22

outcomes will be recorded by the patient. The groups will be marked “A” and “B” when the data are sent to the 23

statistician to ensure that the groups are not recognized as the control group and experimental group. Un-24

blinding of the assessors will be permissible only in the case of a serious adverse event. 25

26

5.2. The rationale for the lack of a sham moxibustion group 27

For the pragmatic purpose of the future study, we decided to reflect the real clinical situation without omitting 28

the patients’ additional time, effort and expectations by comparing patients who receive conventional treatment 29

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with patients who receive both conventional treatment and complementary treatment. A sham or placebo 1

intervention group is the ideal method for efficacy studies with an optimal, strictly restricted design to minimize 2

all influencing factors to prove the efficacy of a specific component of intervention22 23

. Consequently, a sham 3

moxibustion group will not be included in this study. 4

5

6. Interventions 6

6.1. Conventional treatment protocol 7

The conventional treatment will be set as the optimum treatment for each patient to develop a reasonable 8


. 9

The optimum treatment for each patient will be based on the UD’s opinion. The UD will discuss behavioural 10

modifications, such as water intake, with the patient. Watchful waiting will be used for patients without renal 11

insufficiency, urinary retention, recurring infection or complications of bladder-outlet obstruction (BOO). Oral 12

medications will be prescribed when no therapeutic effect is observed after watchful waiting, and the 13

medications will be selected in consideration of overactive bladder, prostate size and prostate-specific antigen 14

(PSA). Preferentially, an alpha-blocker, such as alfuzosin, doxazosin, tamsulosin or terazosin, will be used for 15

functional symptom mitigation. 5-ARIs, such as dutasteride and finasteride, will be used when the prostatic 16

volume is > 40 ml or PSA > 1.4 ng/ml. For cases of a high risk of BPH progression, prostate ≥ 30 mg or PSA ≥ 17

1.5 ng/ml, a combination of an alpha-blocker and a 5-ARI will be used. Anticholinergic agents, such as 18

tolterodine, will be prescribed for patients with overactive bladder but will need to be monitored for patients 19

with ≥ 250 ml post-void residual urine. The conventional treatment components can be changed at the discretion 20

of the UD because this research is a pragmatic study to evaluate the effectiveness and safety of additional 21

moxibustion therapy and the conventional treatment will still be maintained for the last follow-up3 4

. 22

23

6.2. Integrative treatment protocol 24

Moxibustion therapy will be added to the conventional treatment described in section 6.1 twice per week for 25

four weeks. The moxibustion therapy will be conducted by a skilled KMD who has at least two years’ 26

experience in the clinic. The timeframes of the conventional treatment group (CG) and the integrative treatment 27

group (IG) are shown in figure 2. Both the apparatus type and mini-pillar type moxibustion will be used. 28

The apparatus types are a Hatnim-moxa apparatus (Bosungsa, Incheon, South Korea) and a moxa pillar 29

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(Bosungsa, South Korea) that generates 65-70 °C of heat. Moxibustion will be conducted at acupoints CV4 on 1


and 2


26

. Additional gauze will be offered layer by layer when the patient requests it due to 3

intolerable heat. This apparatus-moxibustion will be stopped if the patient complains of intolerable heat even 4

after the additional gauze is offered more than three times. If the patient cannot feel any heat once the moxa 5

pillar is totally burned, the apparatus-moxibustion will be conducted one more time; the procedure can be 6

performed one more time as before, but the number of apparatus-moxibustion applications cannot exceed three. 7

The therapy can be stopped if a second-degree or higher burn occurs even before completing eight treatment 8

sessions. 9

Kanghwa mini-moxa of “lowest” intensity, which generates heat of approximately 45 °C, will be used for mini-10


and LR320 28 29

11

(figure 4). The mini-moxa will be removed when totally burned, which takes approximately 5 minutes, but it 12

may be removed if the patient complains of intolerable heat. The mini-moxa will not be repeated on the acupoint 13

on which moxibustion was stopped per the patient’s request. Repetitive mini-moxa will be performed on the 14

acupoints at which the patient did not feel heat and completed prior mini-moxa for the entire burning period, up 15

to a maximum of seven times on each point. Beginning with the second session, the treated region will be 16

checked and further mini-moxa will not be allowed on an acupoint where a second-degree or higher burn 17

occurred. In this case, the mini-moxa will be re-started after the burn is completely healed. 18


, Liu QG31

19

and Wang Y26

, who reported the effective results and clinical experiences of two KMDs considering practicality 20

in terms of the patients’ general social environment and the accessibility of the hospital. The number of 21

performed moxibustion treatments will be recorded in both the electronic medical record (EMR) and case report 22

form (CRF) at every visit in adherence with intervention protocols. 23


, 24

and in this case, the patient will not be considered a study drop-out. However, if a patient cannot continue the 25

treatment because of discomfort from the moxibustion smoke, allergic response or pigmentation from the moxa-26

soot, he cannot be regarded as having completed the trial. 27

28

6.3. Prohibited or allowed parallel medical treatments 29

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Flexible oral medications according to the discretion of the UD's opinion are allowed to offer the best treatment 1

for each patient; thus, the medications will not be fixed without variation. All types of medication therapy based 2

on AUA guidelines and the Korean prostate society guideline will be allowed. 3

Surgical treatment, including transurethral resection of the prostate (TURP), transurethral incision of the 4

prostate (TUIP), abdominal prostatectomy, minimally invasive therapy using a laser, transurethral needle 5

ablation of the prostate (TUNA), and transurethral microwave thermotherapy (TUMT), are prohibited; therefore, 6

patients who want or are recommended for such therapies cannot participate in this trial. 7

8

6.4. Treatment of adverse events 9

We will disinfect and dress the wound when a second-degree or higher burn occurs and will refer the patient to 10

dermatology to receive proper treatment when a third-degree or higher burn occurs. 11

12

7. Outcome measures 13

7.1 Primary outcome measure 14

The IPSS after 8 sessions will be the primary outcome measure. The results of the IPSS, including the change in 15

IPSS and its standard deviation, will be used to calculate the proper sample size for the future trial by 16

performing a power analysis. IPSS was developed by the AUA in 1992, and a question regarding quality of life 17

(QoL) was later added33


. IPSS consists of seven sub-themes of 18

incomplete emptying, frequency, intermittency, urgency, weak stream, straining and nocturia. The severity 19

scoring is as follows: 0-7, mildly symptomatic; 8-19, moderately symptomatic; and 20-35, severely 20

symptomatic BPH. The separate QoL question requires the respondent to select a QoL category ranging from 21

zero (delighted) to six (terrible). 22

23

7.2 Secondary outcome measure 24

7.2.1. Patient’s global impression of changes (PGIC) 25

The PGIC will be recorded for each patient at every visit after the first treatment. PGIC is a scoring system used 26

to evaluate the level of change from the beginning of the treatment, either conventional or integrative, to the 27

time of the PGIC check. This scale considers limitations of physical activity, symptoms, emotions and QoL in 28

general. The scoring is as follows: no change (or condition has become worse), 1; almost the same, hardly any 29

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change at all, 2; slightly better, but no noticeable change, 3; somewhat better, but the change has not made any 1

real difference, 4; moderately better and a slight but noticeable change, 5; better and a definite improvement that 2

has made a real and worthwhile difference, 6; a great deal better and a considerable improvement that has made 3

a substantial difference, 7. In a similar way, each patient will be asked to circle one of the numbers 0 (much 4

better) to 10 (much worse) written on a straight line that represents the change from the beginning to the time of 5

evaluation35

. 6

7

7.2.2. The short-form 36-question health survey (SF-36) 8

The SF-36 will be checked at the baseline, after 4 sessions, after 8 sessions and after 12 weeks from the baseline. 9

The SF-36 is a commonly used scale to evaluate health-related quality of life (HRQOL). This scale consists of 10

physical function, physical role capability, bodily pain, general health perceptions, vitality, social role capability, 11


. 12

13

7.2.3. The maximum urinary flow rate (Qmax) 14

An independent tester will measure Qmax at baseline and 12 weeks after baseline. Qmax changes from baseline 15

to 12 weeks will be used as an objective outcome measure. Urodynamic study is an invasive method to obtain 16

objective and quantitative data on bladder-outlet function and storage function. Patients will attend the study 17

when they feel a “normal” desire to urinate. The velocity of the external urine stream will be automatically 18

obtained by a calculation using the voided volume and time37

. 19

20

7.2.4. Post-void residual urine volume (PVR) 21

An independent tester will measure PVR at baseline and 12 weeks after baseline. PVR changes from baseline to 22

12 weeks will be evaluated because PVR increases when bladder-outlet function is incomplete37

. PVR will be 23

checked by ultrasonography immediately after the urodynamic study. 24

25

7.2.5. Changing progress and persistency on IPSS 26

The IPSS will be evaluated after 4 sessions in the integrative group to explore the process of change and will 27

be checked 12 weeks after the beginning of the study, after 8 weeks of completed moxibustion therapy, to 28

evaluate the persistency of the effects of moxibustion therapy. This period of 12 weeks was determined based on 29

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a previous study26, the clinical experiences of two KMDs, and the optimum follow-up period recommended in 1

conventional treatment guidelines38-40

. 2

3

7.2.6. Adverse events 4

To explore safety, adverse events will be recorded. At every visit, patients will be asked whether adverse 5

effects have developed and, if so, what types of adverse effects. In particular, second-degree or higher burns and 6

allergic responses of the skin or whole body will be examined thoroughly, and other types of discomfort will be 7

checked. 8

9

7.2.7. The recruitment, compliance and retention rate 10

For feasibility, the recruitment, compliance and retention rate will be recorded. The recruitment rate will be the 11

ratio of the patients who completely meet the inclusion/exclusion criteria and who register for the trial versus the 12

recruitment goal. The compliance rate will be measured by the attendance rate for the treatment phase in the 13

integrative group and the attendance rate for the three major assessments (baseline, visit 9 and visit 10) in both 14

groups. The retention rate is defined as the ratio of 1) the number of patients who attend the primary outcome 15

assessment after four weeks versus the total number of participants, 2) the number of patients who attend the 16

final assessment after 12 weeks versus the total number of participants and 3) the number of patients who return 17

the frequency-volume chart (FVC) versus the total number of participants. 18

19

8. Data collection 20

Subjective outcome measurements will be checked for each patient, and objective outcome measurement data 21

will be preserved in both their original form and as an EMR. These data will be written on the CRF by a 22

certificated clinical research coordinator (CRC). To promote patient retention and completion of follow-up, an 23

honorarium will be provided with a differential rate according to the patients' participation. 24

25

9. Statistical analysis 26

9.1. Analysis of efficacy 27

Both intention-to-treat (ITT) and per-protocol (PP) analyses will be performed. The last observation carried 28

forward (LOCF) method will be used for missing data in ITT analysis. The paired t-test will be used for 29

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intragroup before/after treatment comparisons. The independent t-test will be used for intergroup comparisons. 1

For non-parametric data, the Wilcoxon signed-rank test for intragroup and the Wilcoxon rank-sum test for 2

intergroup test will be used. Categorical data, such as adverse effects, will be investigated by calculating the 3

occurrence rate of adverse events for each group and then performing analysis with the chi-square test or 4

Fisher’s exact test. If statistically significant differences between two groups are observed or covariance is 5

expected, analysis of covariance (ANCOVA) will be used. All of the statistical analysis will be done with two-6

tailed tests, and the significance level will be set as 0.05. To explore feasibility, the recruitment, compliance, and 7

retention rates will be calculated, and the percentages will be reported. Furthermore, subgroup analyses will be 8

performed according to the severity in terms of the IPSS or prostate size and the type of conventional treatment. 9

10

10. Safety 11

Expected adverse events, such as burns and allergic responses, will be recorded along with their modality, date 12

of occurrence, and duration. Patients will report other unexpected adverse events freely. The severity of the 13

adverse events will be categorized according to the WHO 5-grade performance status classification as follows: 0, 14

able to carry out all normal activity without restriction; 1, restricted in strenuous activity but ambulatory and 15

able to carry out light work; 2, ambulatory and capable of all self-care but unable to carry out any work 16

activities and up and about more than 50% of waking hours; 3, symptomatic and in a chair or in bed for greater 17

than 50% of the day but not bedridden; 4, completely disabled, unable to carry out any self-care; totally 18

confined to bed or chair. The cause-and-effect relation between the intervention and adverse events will be 19

assessed according to the WHO-Uppsala Monitoring Centre (UMC) causality categories of 1, certain; 2, 20

probable/likely; 3, possible; 4, unlikely; 5, conditional/unclassified; 6, unassessable/unclassifiable. 21

To minimize the expected adverse events, we will describe the risk of adverse events to patients who have prior 22

allergic responses to moxibustion therapy, allergic rhinitis or allergic conjunctivitis. Patients will be informed to 23

notify the practitioner if they experience such symptoms during the treatment to receive proper and prompt 24

treatment. The treatment will be performed in a well-ventilated room, and a mask will be offered to cover the 25

patient’s mouth and nose. To prevent burns, patients will be educated about indirect moxibustion therapy and its 26

precautions and informed to notify the practitioner promptly if they feel intolerable heat and wish to stop the 27

treatment. The principal investigator (PI) will describe and assess all of the symptoms that occur during the 28

clinical trial and will report to the institutional review board (IRB) to determine whether to continue or stop the 29

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study when serious adverse events occur. 1

Patients who suffer from adverse events will be treated as described in section 6.4. Additionally, patients who 2

suffer harm from this trial participation will be cared for through insurance. All patients will be informed of and 3

sign off on the “regulation concerning subject compensation”, including detailed descriptions of this regulation. 4

5

11. Monitoring 6

The independent data monitoring committee (DMC), composed of one KMD and one clinical research expert, 7

will examine the process of progress and whether the trial follows the study plan, the standard guidelines, and 8

clinical-trials management criteria and other related standards. Monitoring will be conducted by regular visits 9

and phone calls. The DMC will check the original record and case report forms. If any problem is found, the 10

DMC will discuss this with the PI. If any serious problems that could threaten the security of patients are found, 11

the DMC will discuss this with the IRB and PI. The PI will make the final decision as to whether to continue or 12

to terminate the trial, and the IRB can order the PI to terminate the trial in the case of a serious problem. 13

14

12. Ethical considerations and dissemination 15

12.1. Written informed consent and study approval 16

This study was approved by the IRBs of both PNUYH and PNUKH. A signed informed consent will be 17

submitted from each patient to the practitioner. If any changes to the inclusion/exclusion criteria, outcome 18

measure methods or data analysis are demanded, the decision will be made through a discussion between the 19

UD and KMD. The changed contents would need to be reapproved by the IRB and reflected in the patient-20

explanation and study registration (clinicaltrials.gov), and a new consent from the patient would need to be 21

obtained. 22

23

12.2. Private information protection 24

Collected data from patients will be safeguarded with specific serial numbers without any personally identifiable 25

information so that nobody can recognize the patients except a security manager who has a code-table. 26

Computer-stored personal information will be secured using a password, and all matters related to security will 27

be supervised by the PI. Publication will not include any personally identifiable information, and data will be 28

treated anonymously. Strict security is assured even in a case of a patient dropping out mid-study and after the 29

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end of the study. 1

Data used for the study will be disposed of after the collection of materials for a research paper. Computer 2

storage files will be deleted and documents will be shredded on 31st November, 2017. 3

The PI, a monitor and an inspector can read the patients’ records for the purpose of monitoring and progress 4

oversight in terms of laws and ethics. These data will be stored securely in the National Clinical Research 5

Center for Korean Medicine. This matter will be explained to patients, who will also be provided a written 6

explanation. 7

8

12.3. Dissemination 9

The trial results will be disseminated through open-access journals and conferences. 10

11

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DISCUSSION 1

2 This study is the first protocol of a randomized controlled pilot trial in Korea to evaluate the feasibility of 3

moxibustion as an adjuvant to conventional therapy in BPH accompanying LUTS by exploring its effectiveness 4

and safety. 5

The medical system of South Korea has been maintained as a dualized system since the revival of KMD by the 6

enactment of the National Medical Insurance Act in 1951. This system has had some negative aspects, such as 7

the incautious use of medicine combinations and distrust between the two medical fields; however, it has had 8


. Therefore, 9

the necessity of integrative medicine has been propounded steadily to establish a new medical system combining 10


. 11

This study was designed as an investigation of add-on treatment without a placebo control because methods of 12

additional alternative treatments in conjunction with the conventional treatment are considered appropriate in 13


. Despite relatively acceptable rates of adverse 14

events, increased side effects caused by the combination of different types of oral drug4 and by patient 15

vulnerability factors, such as ageing and underlying disease, still must be investigated. Therefore, the 16

effectiveness and safety of adjuvant treatments should be evaluated, after which the adjuvant treatment may be 17

considered for intractable urinary disorders including interstitial cystitis and chronic prostatitis. Additionally, a 18


. Thus, we set 19

broad inclusion/exclusion criteria and flexible interventions allowing for different treatment regimes according 20

to each patient’s medical condition. In addition, conventional oral medication is not restricted to one type 21

considering the pragmatic purpose and the study ethics. The moxibustion therapy has the limitation of 22

inconvenience because patients must visit the hospital for every treatment, while the conventional oral 23

medication can be provided once for a relatively long period; thus, the experts discussed and decided to perform 24

a relatively short-period treatment and to follow up after 12 weeks, as in conventional treatment38

25

This study has some limitations. The 12-week follow-up was set according to the routine check period of 26

conventional treatment but was not sufficient to evaluate the long-term effects. Furthermore, the development of 27

changes cannot be investigated because frequent and regular IPSS checks were not planned in this trial. 28

Therefore, future trials should include more frequent and regular outcome assessments in both groups and a 29

longer follow-up period of at least one year in order to investigate the development of changes in each group 30

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and the persisting effect so that the treatment sessions, period and interval can be properly modified for the final 1

integrative treatment guideline. Another limitation is that the prostate size is not included as an outcome 2

measurement because the feasibility is the main focus rather than definitive assessment of effectiveness. 3

Therefore, studies evaluating the effect of the combined treatment on prostate size should be conducted after the 4

LUTS-reduction effect is demonstrated. Future power analysis studies should be performed by determining the 5

effect size based on the results of this study, and cost-effectiveness studies should be performed to provide 6

important details for decision-makers. 7

8

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TRIAL STATUS 1

2 This study is currently in the recruiting phase. The first patient was enrolled on March 10, 2014, data collection 3

will be complete in approximately December 2015, and the article including results is expected in 4

approximately 2016. 5

6

7

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Acknowledgements 1

This manuscript was edited by American Journal Experts. 2

3

Funding 4

This study was supported by a Grant from the Korea Institute of Oriental Medicine (K15042). 5

6

Lee Jun Hwan. M.D./ Ph. D 7

Clinical Research Division 8

Korea Institute of Oriental Medicine 9

10

Address: 1672 Yuseong-daero, Yuseong-gu, Daejeon, 305-811, Republic of Korea 11

Tel: +82-42-868-9693 12

E-mail: [email protected] 13

14

Contributors 15

JNK, SDL and JGN conceived the study. JNK, SDL, JKN, JYH, YJY and HYL initiated the study design, and 16

DHL, SHP, JHL and HLP helped with its implementation. JKN, DHL, JHY and HYL performed the intervention 17

and discussed the optimal complementary medicine. HYL drafted the study protocol manuscript. All authors 18

contributed to the refinement of the study protocol and approved the final manuscript. 19

20

Competing interests 21

No, there are no competing interests. 22

23

Access to data 24

The data from this trial will be accessible by contacting the corresponding author. 25

26

Ethics approval 27

The study was approved by IRBs of both Pusan National University Korean Medicine Hospital (IRB approval 28

number 2013021) and Pusan National University Yangsan Hospital (IRB approval number 03-2013-013). 29

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Table 1. Trial progress 1 2 Period Screening Active treatment F/U

Visit Screening 1 2 3 4 5 6 7 8 9* 10

Week 0 1 2 3 4 12

Consent ●


Medical history ● ○ ○ ○ ○ ○ ○ ○ ○ ● ●

Vital signs ● ○ ○ ○ ○ ○ ○ ○ ○ ●


Conformity

assessment

●

Check PSA ●

Check prostate size

(TRUS)

●

Inclusion/exclusion

criteria

●


visit schedule

● ○ ○ ○ ○ ○ ○ ○ ○ ○

Randomization ●


IPSS ● ○ ● ●

SF-36 ● ○ ● ●

PGIC ○ ○ ○ ○ ○ ○ ○ ● ●

Qmax ● ●

PVR ● ●

FVC ● ●

Adverse event

monitoring

○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Final compliance

assessment

●







3 Table 2. International prostate symptom score 4

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1

No

t at

all

Les

s th

an

1 t

ime

in 5

Les

s th

an

hal

f th

e ti

me

Ab

ou

t h

alf

the

tim

e

Mo

re t

han h

alf

the

tim

e

Alm

ost

alw

ays

Incomplete emptying



urinating?

0 1 2 3 4 5

Frequency



0 1 2 3 4 5

Intermittency



0 1 2 3 4 5

Urgency


postpone urination?

0 1 2 3 4 5

Weak stream


urinary stream?

0 1 2 3 4 5

Nocturia

No

ne

1 t

ime

2 t

imes

3 t

imes

4 t

imes

5 t

imes

or

mo

re




0 1 2 3 4 5


Del

igh

ted

Ple

ased

Most

ly

sati

sfie

d

Mix

ed –

ab

out

equal

ly

Most

ly

dis

sati

sfie

d

Un

hap

py

Ter

rible



feel about that?

0 1 2 3 4 5 6

Total score: 0-7, mildly symptomatic; 8-19, moderately symptomatic; 20-35, severely symptomatic. 2

3

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Figures 1 2 Figure 1. Trial flowchart 3 4

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1 Figure 2. Timeframe of the integrative treatment group (IG) and conventional treatment group (TG). 2 3

4 5

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Figure 3. Apparatus-type moxibustion on CV4 1

2

3

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Figure 4. Mini-pillar-type moxibustion on bilateral SP6 and LR3 1 2

3

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32



number

NCT02051036


Registry

01/26/2014.



Support












Studied






Inclusion criteria:






Exclusion criteria:














1 2

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148x186mm (96 x 96 DPI)

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298x133mm (96 x 96 DPI)

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267x155mm (96 x 96 DPI)

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264x161mm (96 x 96 DPI)

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1










Roles and

responsibilities






______25______




______25______

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2

Introduction

Background and

rationale



______5_______





______6_______




______7_______



______8_______


administered

______10______



______10,11____



______11______

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial ______11,12____





______12-14__



______7______

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3



______7,8____



Allocation:

Sequence

generation





______7__ ____

Allocation

concealment

mechanism



_______7______


interventions

_______7______



_______9-10___



_______9-10___


Data collection

methods





_____12- 14_____



_______14______

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4




______16-17__



______14-15___




______14______

Methods: Monitoring




needed

______15______



______15______



______14______



_____14,15_____


Research ethics

approval


Protocol

amendments



regulators)

______15______

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5


how (see Item 32)

______7,16_____



_____none_____



______16______

Declaration of

interests




______25______

Ancillary and post-

trial care


participation

______15,16___




______17______



Appendices

Informed consent

materials


Biological

specimens



___ __




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