The present protocol was designed according to Standard Protocol Items: Recommendations
for International Trials 2013 (SPIRIT 2013: see online supplementary file S1). This
trial is a randomized, double-blind, placebo-controlled, single-center study, which
has been authorized by the MFDS (approval number 31617) and registered with the Korean
Clinical Trial Registry (KCT0003115). This trial will be conducted at Kyunghee University
Korean Medicine Hospital. A flowchart of the study is shown in Figure 1.
Figure 1. Study flowchart
This trial has been approved by the Institutional Review Board of the Kyunghee University
Korean Medicine Hospital (KOMCIRB 2018-05-017-001). The protocol complies with both
the Declaration of Helsinki and Good Clinical Practice Guidelines. All eligible patients
have to provide their signed informed consent prior to enrollment.
Recruitment
Thirty participants with reflux-induced chronic cough will be recruited through advertisements
and referrals in Kyunghee University Korean Medicine Hospital. The participants deemed
eligible in screening of the inclusion and exclusion criteria will be recruited as
study subjects and assigned to the experimental and control groups as per 1:1 ratio.
Each group will be prescribed a drug for 6 weeks.
Participants
Inclusion criteria
We will include participants who 1) are between 19 and 70 years of age; 2) have a
history of cough continuously for >8 weeks; 3) have been diagnosed with reflux esophagitis
within the last 1 year; and 4) have provided written consent to the clinical trial
agreement.
Exclusion criteria
Participants will be excluded from the study if they 1) present with abnormal findings
as established by the chest x-rays, pulmonary function test (PFT) with bronchodilator
test, fractional exhaled nitric oxide (FeNO), and nasal endoscopy, that might lead
to cough; 2) were diagnosed with acute respiratory diseases (including upper respiratory
tract disorders) within the last 1 month; 3) were diagnosed with chronic respiratory
diseases (e.g., chronic obstructive pulmonary disease, bronchial asthma, bronchiectasis,
interstitial lung disease, and other chronic respiratory diseases) within the last
2 years; 4) were diagnosed with LA grade C or higher GERD within the last 1 year;
5) exhibit symptoms indicative of malignant disease within the gastrointestinal tract
(e.g., severe dysphagia, bleeding, weight loss, anemia, bloody stools); 6) history
of surgical or endoscopic anti-reflux treatment; 7) Currently, are suffering from
a disorder, such as postnasal drip syndrome, active infection requiring systemic antibiotic
therapy, or a blood-clotting disorder; 8) have a lifetime smoking history of ≥20 packs
(400 cigarettes); 9) have used an angiotensin-converting-enzyme inhibitor during the
previous 4 months; 10) have used cough medicines, glucocorticoids, leukotriene receptor
antagonists, anticholinergic drugs, long-acting β2 agonists, antihistamines, proton
pump inhibitors, histamine receptor antagonists, mucosal protective agents, gastrointestinal
motility promoters, antacids, antidepressants, anxiolytics, lower esophageal sphincter
agonists, or any herbal medication within the previous 2 weeks; 11) have allergies
or sensitivities to the experimental medicine/placebo; 12) have a body mass index
(BMI) <18.5; 13) have an aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) level at least two-fold higher than the upper normal limit or a serum creatinine
level at least 1.2-fold the upper normal limit; 14) have a mean cough diary score
of <2 during the 1-week run-in period; 15) record <10 entries in the cough diary during
the 1-week run-in period; 16) have a history of malignant tumors (e.g., lung or esophageal
cancer) within the last 5 years; 17) are excessive drinkers; 18) are pregnant or breastfeeding;
19) do not consent to use birth control during the trial; 20) participated in clinical
trials for the same disease within the past 3 months; or 21) are deemed unsuitable
by the investigators.
Rejection and withdrawal criteria
The rejection and withdrawal criteria will be as follows: 1) treatment that could
affect the clinical trial results without any instruction by the investigator; 2)
failure to adhere to the protocol or compliance rate <80%; 3) a serious adverse event
(SAE) during the trial; 4) voluntary withdrawal from the trial; 5) use of drugs such
as steroids, persistent bronchodilators, and anti-leukotriene, anticholinergics, proton
pump inhibitors, histamine receptor antagonists, mucosal protective agents, gastrointestinal
motility promoters, antacids, antidepressants, anxiolytics, and lower esophageal sphincteric
agonist preparations during clinical trials; 6) use of any herbal medications; 7)
any other reasons deemed inappropriate by the investigators.
Intervention
OJS plus SMS
Subjects in the intervention group will be administered a total 5.76 g of OJS (4.35
g/each) plus SMS (1.41 g/each) granules. The participants will be instructed to consume
these granules three times per day for 6 weeks. The dosage is based on the requirements
of the MFDS. The OJS and SMS granules are manufactured by Han Kook Shin Yak Pharm
Co. Ltd. (Nonsan, Chungnam, Republic of Korea), a company that has obtained authorization
from the Korea Good Manufacturing Practice. Both the OJS and SMS granules and their
ingredients have been approved by the MFDS. These ingredients are presented in Table
1. Voucher specimens will be reserved at the research library of Han Kook Shin Yak
Pharm Co. Ltd.
Table 1. Composition of Ojeok-san and Saengmaek-san
Placebo
The control group will receive a total of 5.76 g of OJS and SMSplacebo granules.The participants will be instructed to consume these granules three times per day
for 6 weeks.The placebo is manufactured by the Han Kook Shin Yak Pharm Co. Ltd. in accordance
with the placebo guidelines of the MFDS. Although granules do not contain active ingredients, their appearance, taste, and
aroma are similar to the experimental intervention granules. The OJS and SMS placebos comprise of starch, lactose, citric acid, caramel color,
and ginseng flavor powder.
All products were packaged by Han Kook Shin Yak Pharm Co. OJS and SMS are packaged
in 4.35 and 1.41 g, respectively, and each placebo is packaged in the same amount.
OJS and SMS or OJS placebo and SMS placebo will be provided to each randomized participant
at visits 1 (week 0 ± 3 days), 2 (week 2 ± 3 days), and 3 (week 4 ± 3 days). The clinical
trial drugs and placebo will be stored at the Korean medical clinical trial center
(K-CTC) clinical research pharmacy in Kyunghee University Korean Medicine Hospital.
An independent and a well-trained pharmacist will be responsible for all the procedures
related to drugs. The study process is outlined in the Figure 2.
Randomization and allocation concealment
Participants will be assigned randomly in 1:1 ratio to the intervention group (OJS
plus SMS group) and control group (placebo group). An independent statistician will
conduct participant randomization using a randomization table created with SAS version
9.1.3 for Microsoft Windows (SAS Institute Inc., NC, Cary, USA). After receiving an
explanation of the study and providing a consent form to participate in the clinical
trial, each subject will be given a screening number (S□□-□□□) in order. Subjects
who are finally selected to participate in the clinical trial following the screening
test and 1-week window period will be given a registration number (R□□ - □□□). A third
party will allocate each subject to a group according to the registration number and
the random assignment table.
Blinding
The drug and placebo will be administered by code and by double-blind methods in which
the investigator and the participants will not know whether the drug is a test drug
or a reference drug. Additionally, the clinical trial pharmacist will be blinded to
the treatment allocation. For this purpose, placebo will be made similar to the experimental
medicine with respect to the characteristics, taste, and flavor. The medicine manufacturers
directly label the code assigned to the experimental medicine and placebo, and the
third party matches the generated random number and code. When a third party registers
each study subject, it sends the test number or the control number of the matching
test drug to the researcher by telephone, text message, mobile communication application,
etc., according to the random number assigned. When a severe or medically significant
event occurs, the statistician will uncover the blinding,
Outcome measures
Primary outcome measurement
The primary outcome will be the cough diary score at week 6. The mean cough symptom
score in the cough diary during 1-week run-in period will be set as the baseline score
of each participant enrolled in and randomized for the trial.
The cough diary is an evaluation scale that divides the severity and frequency of
cough into five stages [21]. The subjects will conduct self-evaluations twice daily,
and the cough diary will be prepared at 20:00 (daytime, 08:00–20:00) and at 8:00 (nighttime,
20:00–8:00). Patients will be required to evaluate their symptoms twice per day (daytime
and nighttime). Cough frequency will be graded on a five-point scale as follows: 0,
no cough; 1, infrequent/occasional; 2, several times; 3, many times; and 4, all the
time. Cough severity will be graded on a five-point scale as follows: 0, Symptom is
not present.; 1, Symptom is present; is not a problem; does not interfere/hinder activity/
interactions/sleep in any way; 2, Symptom is present; is somewhat of a problem; may
interfere/hinder certain activities/interactions/sleep; 3, Symptom is present; is
a problem; frequently interferes/hinders many activities/interactions/sleep; and 4,
Symptom is present; is a major concern; very frequently interferes/hinders most activities/interactions/sleep.
The total cough score (range: 0–8) is the sum of the daytime and nighttime cough symptom
scores.
Secondary outcome measurement
Cough visual analog scale (VAS): The cough VAS is a rating scale that rates the degree
and frequency of coughing on a scale of 0–10 points, with 0 indicating "no cough"
and 10 indicating "unbearable cough". After study registration, the investigator will
provide each subject with a 2-week self-recording diary at baseline and weeks 2, 4,
and 6. The participants will record daily entries and return the data to the investigators
on weeks 2, 4, 6, and 8, respectively.
Leicester Cough Questionnaire (LCQ-K): The LCQ is a 19-item questionnaire that is
used to measure the quality of life according to the cough [22]. These 19 items are
divided into three parts: physical, mental, and social. Each item score ranges from
1 to 7 points, and a higher score indicates better health. We will use the validated
LCQ-Korean version [23].
Gastrointestinal Symptom Rating Scale (GSRS): The GSRS is a widely used and validated
self-reported GI symptom scale. It includes 15 symptom items grouped into five symptom
areas that can be scored on a seven-point scale [24].
Hull Airway Reflux (hypersensitivity) Questionnaire (HARQ): The HARQ is a self-reported
tool that is used to measure airway hyper-responsiveness due to laryngopharyngeal
reflux. Symptoms of airway hypersensitivity caused by laryngeal reflux are grouped
into 14 items. Each item is scored on a range of 0–5 points, with a maximum total
score of 70 points [25].
Pattern Identification for Chronic Cough Questionnaire (PICCQ): The PICCQ is a tool
used to identify patterns of chronic cough. Chronic cough is, thus, classified into
four patterns: wind-cold, phlegm-turbidity, fire-heat, and deficiency (lung deficiency
and kidney yang deficiency) [26].
Pattern Identification for GERD: This tool is used to analyze the distribution of
pattern in patients with GERD, who complain of cough as the main symptom. Four GERD
patterns have been identified: pattern/syndrome of liver qi invading the stomach,
spleen-stomach weakness, spleen-stomach dampness-heat, and stomach yin deficiency
[27].
Safety and adverse event outcomes
Safety
Safety will be assessed using adverse reaction reports and clinical laboratory tests.
Liver function tests include AST, ALT, alkaline phosphatase, total bilirubin, and
γ-glutamyl transpeptidase levels, and renal function tests include blood urea nitrogen
and creatinine levels. Women of childbearing age will be tested for pregnancy.
Adverse events
An adverse event (AE) is an undesirable and unintended sign, symptom, or disease that
does not necessarily have a cause-and-effect relationship with the intervention evaluated
in a clinical trial. We will continuously monitor subjects for AEs and make all related
decisions based on both objective and subjective signs, as well as blood test results.
SAE referred to any of the following AEs occurring in a participant during the clinical
trial: 1) death or danger to life; 2) hospitalization or extension of hospital stay
due to an adverse event; 3) permanent or significant failure or degradation of function;
4) development of fetal malformations or abnormalities; 5) other medically important
situations. The investigator rapidly reports all SAEs to the sponsor (usually within
24 hours), in order to: 1) ensure patient safety at clinical trial, and 2) meet the
MFDS guideline for reporting. The investigator also reports to the Institutional Review
Board.
Data collection, management, and monitoring
Data and instrumental measurements will be collected from all subjects at every visit
using a paper-based case report form. Data entry and management will be completed
by an independent data administrator to ensure data accuracy. All procedures will
comply with the confidentiality standards for medical data. All documents related
to the conduct of clinical trials will be retained by the principal investigator or
sub-investigator. The participants’ information will be maintained in the storage
for a period of 3 years after study completion. Important protocol modifications during
this study will be communicated to the Institutional Review Board, trial registry,
investigators, trial participants, and the journal of publication. An independent
monitoring supervisor affiliated with the Kyunghee University Korean Medicine clinical
trial center would be assigned to contact and visit the researchers regularly and
thus supervise the trial process.
Sample size
This is a pilot study that examines the feasibility of conducting a large-scale randomized
clinical trial of OJS plus SMS for treating chronic cough in patients with GERD. A
pilot study for planning a larger study and estimating its effective size requires
an adequate small sample size. We calculated the minimum number of recruiters required
for a preliminary study according to the general rule [28]. Each group would require
12 participants with a power of 80% and α-value of 0.05. Assuming a total withdrawal
and dropout rate of 20%, we estimated that a total sample size of 30 patients would
be required.
Statistical analysis
Statistical analysis will be performed using the SPSS statistical package (ver. 18.0;
IBM, Inc., Armonk, NY, USA), and the level of significance will be established at
α = 0.05. An independent professional statistician will carry out the data analysis.
The intent-to-treat (ITT) analysis will be used as the main analysis, and subordinately
we will present per-protocol analysis. The ITT population will include all participants
who have been treated with at least one dose of the study drug and who record and
keep a minimum of one day's cough diary. The cough diary will be used to compare the cough symptom scores at 6 weeks (visit
4). If the normality test is satisfied, the independent t-test will be used; otherwise,
Mann–Whitney U test will be used. However, an analysis of covariance (ANCOVA) will
be performed if significant differences in the baseline cough diary values are found
between the groups. Inter-group comparisons of cough VAS will be evaluated on weeks
2, 4, and 6. Mean differences in the LCQ-K, GSRS, and HARQ scores will be evaluated
at baseline and week 6. Missing values will be replaced by the last observed value
of each subject according to the “last observation carried forward (LOCF)” method.