Efficacy and safety of Maekmoondong-tang for chronic dry cough: a study protocol for a randomized controlled trial

Objective

The objective of this trial is to assess the efficacy and safety of MMDT for the adult
patients with chronic dry cough.

Hypothesis

We primarily hypothesize that 4 weeks of MMDT intervention eases chronic dry cough
in adults more efficaciously than a placebo control. We will evaluate this hypothesis
using a 10-point cough diary.

Design

This study is an exploratory, single-center, placebo-controlled, double-blind, randomized,
parallel group clinical trial. Figure 1 shows a flow chart of the study. Eligibility for the study will be decided on the
basis of a daily cough diary, which participants will keep during the 1-week run-in
period. Those with a cough diary symptom score of more than 2, as well as more than
10 entries in the cough diary during the run-in period, will be enrolled pending the
inclusion and exclusion criteria below.

Fig. 1. Study flow chart

Participants

Inclusion, exclusion, and withdrawal criteria

The inclusion criteria are: (1) age between 19 and 75 years; (2) chronic cough that
has lasted more than 8 weeks; (3) dry cough (sputum frequency of 5 or fewer times
per day, and sputum volume less than 10 ml per day, on the basis of the Sputum Severity
Evaluation Standard of the Korean Ministry of Food and Drug Safety); (4) provision
of written informed consent.

The exclusion criteria are: (1) abnormal pulmonary function test (forced vital capacity,
or forced expiratory volume in 1 s, 80 % of predicted); (2) abnormal chest X-ray;
(3) acute respiratory disease, including upper respiratory tract infection, during
the previous 4 weeks; (4) chronic pulmonary diseases (COPD, idiopathic pulmonary fibrosis,
bronchiectasis, etc.) during the previous 2 years; (5) diagnosis of malignant tumor
during the previous 5 years; (6) history of smoking (?20 packs [400 cigarettes] during
the participants’ lifetime); (7) treatment taking an angiotensin-converting-enzyme
inhibitor at present or during the previous 4 months; (8) current or the precious
2-week use of antitussive drugs, glucocorticoids, leukotriene receptor antagonists,
anticholinergic drugs, long-acting ?2 agonists or any herbal medication; (9) antihistamine
treatment during the previous 3 days; (10) aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) levels at least twofold higher than the upper normal limit,
or a serum creatinine levels at least 1.2-fold the upper normal limit; (11) a mean
cough diary score of less than 2 during the 1-week run-in period; (12) fewer than
10 entries in the cough diary during the 1-week run-in period; (13) pregnancy or breastfeeding;
(14) illiteracy or cognitive impairment; (15) unsuitability as judged by the investigators.

The rejection and withdrawal criteria are: (1) treatment that might influence the
results of the trial without the agreement of an investigator; (2) use of forbidden
drugs, such as antitussives, glucocorticoids, leukotriene receptor antagonists, anticholinergics,
and long-acting ?2 agonists; (3) participants not following the protocol, or taking??80
% of the prescribed doses; (4) a serious adverse event (SAE) during the trial; (5)
voluntary withdrawal from the trial; (6) unsuitability as judged by the investigators.

Recruitment

Through advertisements and referrals, a total of 58 patients with chronic dry cough
will be recruited at the Korean Medicine Clinical Trial Center (K-CTC) of the Kyung
Hee University Korean Medicine Hospital.

Ethics

This trial has been authorized by the Institutional Review Board of the Kyung Hee
University Korean Medicine Hospital (approval number: KOMCIRB-150213-HRBR-007). The
protocol accords with both the Declaration of Helsinki and Good Clinical Practice
(GCP) Guidelines. Signed informed consent forms will be obtained from all eligible
participants before enrollment.

This trial is registered with the Korean Clinical Trial Registry (registration number:
KCT0001646).

Randomization and Concealment

An independent statistician who is unware of the design and purpose of the study will
generate a randomization table using R software (version 3.2.0; The R Foundation for
Statistical Computing); specifically, a block size of 4 will be used, and the 58 patients
will be randomly allocated group in a 1:1 ratio either to the MMDT treatment group
or to the placebo control. The statistician will keep the randomization lists and
inform the researcher of the matching cord number either by text message or via mobile
communication application.

Blinding

Participants, investigators, and the clinical trial pharmacist will be blinded to
the treatment allocation throughout the course of the study. The placebo granules
will be similar to the MMDT granules in appearance, taste, and scent. The manufacturer
will label the random and product codes on the packaging, and the code labeling will
conform to the GCP guidelines. The clinical trial pharmacist at the K-CTC will provide
the packaged drugs to the patients on the basis of the randomization number. The statistician
will uncover the blinding when necessary, such as an SAE occurs. A blinding test will
be conducted to evaluate the success of blinding after 4 weeks of intervention.

Intervention

MMDT

The MMDT group will receive MMDT granules (3 g/pouch, 3 times per day—before each
meal—for 4 weeks; dosage based on the requirements of the Korean Ministry of Food
and Drug Safety). The MMDT granules are manufactured as “Maekgeuron Granules” by Hanpoong
Pharm Food Co. Ltd. (Jeonju, Republic of Korea), a company that has obtained Korea
Good Manufacturing Practice authorization. Both the MMDT granules and their ingredients
have been approved by the Korean Ministry of Food and Drug Safety. Three grams (dry
weight) of granules (water-extracted MMDT combined with starch and lactose) contain
six herbs: Ophiopogonis Tuber (Liriope platyphylla Wang et Tang, family Liliaceae; 3.33 g), Pinelliae Tuber (Pinellia ternata Breitenbach, family Araceae; 1.67 g), Glycyrrhizae Radix (Glycyrrhiza uralensis Fischer, family Leguminosae; 0.67 g), Zizyphi Fructus (Zizyphus jujuba Miller var. inermis Rehder, family Rhamnaceae; 1.00 g), Ginseng Radix (Panax ginseng C. A. Meyer, family Araliaceae; 0.67 g), and Oryzae Semen (Oryza sativa Linné, family Gramineae; 3.33 g). This 10 g mixture yields 2.07 g of soft extract
after boiling in water. With starch and lactose added, the final MMDT of 3 g is obtained
by drying under reduced pressure. Each 3 g dose of MMDT contains 3.1 mg of glycyrrhzin
acid and 0.31 mg of gincenoside Rb1 (Rg1). Voucher specimens will be reserved at the
research library of Hanpoong Pharm Food Company.

Placebo

The control group will receive placebo granules (3 g/pouch, 3 times per day—before
each meal—for 4 weeks). The placebo was manufactured by the Jeonnam Bioindustry Foundation
Food Research Center (JBF), following the placebo guidelines of the Korean Ministry
of Food and Drug Safety. The granules do not contain any active ingredients, but are
similar in appearance, taste, and scent to the MMDT granules.

All products were packaged by JBF (Naju, Republic of Korea). Either Forty-two MMDT
or placebo pouches will be provided to each randomized participant at visit 1 (week
0?±?3 days) and visit 2 (week 2?±?3 days). The products will be stored at the K-CTC
clinical research pharmacy in Kyunghee University Korean Medicine Hospital, and an
independent and trained pharmacist will manage all procedures associated with the
drugs. The study process is outlined in Table 1.

Table 1. Study process: treatment and outcome measurements

Concomitant and forbidden drugs

If participants experience unbearable cough at night, taking one capsule acetylcysteine
is permitted; this antitussive will be delivered to the patients along with the MMDT
or placebo granules. If this does not improve the cough, the participant will visit
the K-CTC for examination and appropriate management. The participants will be asked
to record whether they take the antitussive agent or not. Other drugs that alleviate
cough—such as other antitussives, glucocorticoids, leukotriene receptor antagonists,
anticholinergics, short-acting ?2 agonists, long-acting ?2 agonists, and antihistamines—are
prohibited. Drugs which are not related to cough symptoms will be permitted. The name,
duration, and dosage of any other drugs taken will be recorded in the case report
forms.

Outcome measures

Primary outcomes

The primary outcome is the cough diary score at week 4. The cough diary score on the
last day of the 1-week run-in period will be taken as the baseline score of participants
who will be enrolled and randomized for the trial.

The cough symptom scoring recommended by Spector et al. will be used in this study
27]. The daily cough diary consists of two parts: daytime (08:00–20:00) and nighttime
(20:00–08:00) cough symptoms. Patients will be required to evaluate their symptoms
twice per day (daytime and nighttime). Daytime cough symptoms will be graded from
zero to five as follows: 0—no cough; 1—cough for one short period; 2—cough for two
or more short periods; 3—frequent coughs that did not interfere with usual daytime
activities; 4—frequent coughs that did interfere with usual daytime activities; and
5—distressing coughs for most of the day. Nighttime cough symptoms will be graded
from zero to five as follows: 0—no cough during the night; 1—cough on waking only;
2—waking once or early precisely because of cough; 3—waking frequently due to cough;
4—wakefulness for most of the night due to cough; and 5—distressing coughs preventing
sleep. The total cough score (from 0 to 10) is the sum of the daytime and nighttime
cough symptom scores.

Secondary outcomes

Cough visual analog scale

The cough VAS is an overall rating scale for cough frequency and severity ranging
from 0 (no cough) to 10 (unbearable cough). The scale will be checked at baseline,
and at weeks 2, 4, and 6 (follow-up visit). The cough VAS mean scores will be recorded
at weeks 2, 4, and 6.

The Leicester Cough Questionnaire (Korean version)

The Leicester Cough Questionnaire (LCQ) is widely used to measure quality of life
in cough patients. It was developed by Birring 28], and has been validated in several languages, including Korean (LCQ-K) 29]. The LCQ comprises three domains: physical, mental, and social quality of life; a
total of 19 items are scored on 7-point Likert scales. A higher score indicates a
more healthy state. Several studies 2], 30], 31] have demonstrated a correlation between cough symptom severity and LCQ score. At
week 4, we will compare the MMDT and placebo groups in terms of mean LCQ-K scores.

Pattern Identification for Chronic Cough Questionnaire

The Pattern Identification for Chronic Cough Questionnaire (PICCQ) is used to identify
patterns in chronic cough patients. We developed this questionnaire using the Delphi
method 32], and conducted clinical research to confirm its validity and reliability. The PICCQ
consists of four patterns: wind-cold, phlegm-turbidity, fire-heat, and deficiency
(lung deficiency and kidney yang deficiency). The PICCQ comprises 38 items scored
on 5-point Likert scales. A patient’s pattern is calculated by summing the scores
of each item. We will investigate the chronic cough pattern distribution in chronic
dry cough patients, as well as the correlation between chronic cough pattern and the
efficacy of MMDT.

Cold-Heat Pattern Questionnaire

We will use the validated Cold-Heat Pattern Questionnaire, which consists of 20 symptom
items (10 items to assess cold pattern and 10 to assess heat pattern) 33]. Each item requires only a “yes” or “no” response depending on the patient’s tendencies
during the previous week. The total numbers of items that a participant responds ‘yes’
will be the cold or heat pattern score, respectively, for the responder. We will investigate
the Cold-Heat Pattern in chronic dry cough patients, as well as the correlation between
the cold-heat pattern scores and the efficacy of MMDT.

Yin Deficiency Scale

We will use the validated yin deficiency scale developed by Park 34]. This questionnaire consists of 27 items, each of which uses a 7-point Likert scale;
the cut-off point was defined as 10 points. We will use the yin deficiency scale to evaluate chronic dry cough patients, as well as to investigate
the correlation between the yin deficiency pattern and the efficacy of MMDT.

Biomarkers

Biomarkers that reflect chronic cough and airway inflammation 35] will be evaluated. These include blood neutrophils, eosinophil counts, serum immunoglobulin
E levels, sputum eosinophilic cationic protein levels, and proinflammatory cytokines
such as tumor necrosis factor alpha, interleukin (IL)-4, IL-5, IL-8, IL-10, and IL-13.

Adverse event reporting

An adverse event (AE) is an undesirable, 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 carry out continuous monitoring of AEs and make any decision
in this regard on the basis of both objective and subjective signs, as well as blood
test results. Appropriate measures will be taken immediately to minimize any SAEs.

Safety outcomes

Safety will be investigated using adverse reaction reports and clinical laboratory
tests; namely, liver function tests (AST, ALT, alkaline phosphatase [ALP], total bilirubin
[TB], and ?-glutamyltranspeptidase [GGT] levels), renal function tests (blood urea
nitrogen [BUN] and creatinine levels), and serum sodium and potassium levels. All
women of childbearing age will also undergo human chorionic gonadotropin testing.

Sample size calculation

We referred a randomized controlled trial (RCT) that was conducted to demonstrate
the clinical efficacy of a herbal medication for the patients with cough variant asthma
(CVA) 36]. It was inevitable because no RCTs have been carried out that address the comprehensive
chronic cough symptom using a herbal mediation. Furthermore, the main manifestation
of CVA is cough lasting more than 8 weeks without any abnormal pulmonary functions;
this is very similar to clinical characteristics of the eligible participants recruited
in this study.

Using a cough diary score, the CVA study compared the efficacy of a herbal medicine
with that of standard therapy (leukotriene receptor antagonist combined with methylxanthine)
for 2 weeks. The calculated effect size was 0.699 (??=?0.05, 1-??=?0.8, 2-tailed test).
Because of the discrepancy in comparators and study duration between the previous
and planned studies, we determined to eliminate the effect of standard therapy and
add the effect of longer treatment duration; this resulted in an adjusted effect size
of 0.85. Assuming a 20 % dropout rate, and an allocation ratio of 1, we have calculated
the necessary sample size to be 58 participants (29 in each group). The above calculations
were performed using G*Powerâ„¢ software (ver. 3.1.9.2) for Mac.

Statistical analysis plan

Data entry and management will be completed by an independent data administrator to
ensure data accuracy. We will analyze the efficacy and safety of MMDT using the “intent-to-treat”
(ITT) principle. Subordinately, we will also present the results of the analysis based
on the “per protocol” principle.

Patient groups for data analysis

Intent-to-treat population

The ITT population will include all participants treated with at least one dose of
the study drug and who keep and return a daily cough diary for at least one day of
recordings.

Per-protocol population

The per-protocol population will include patients who take more than 80 % of the prescribed
doses of the study drug, fill in the daily cough diary on 80 % of the study days,
and return their diary to the researchers.

MMDT responder/non-responder groups

An MMDT treatment responder is defined as a participant who exhibits a 75 % decrease
in cough diary score after 4 weeks of treatment; all other participants in the MMDT
treatment group will be included in the non-responder group. We will analyze the correlations
between MMDT responder group and all TKM patterns.

Statistical analysis

Descriptive statistics will be used for continuous variables, and frequencies for
categorical variables. The “last observation carried forward” (LOCF) principle will
be used to compensate for missing data. The LOCF principle involves replacement of
missing data with the last observed value to obtain a complete database.

When the assumption of normality is satisfied will a t-test be used to compare the two groups in terms of the primary outcome (mean cough
diary score at week 4). Otherwise, the Mann–Whitney U-test will be used. Other continuous variables, such as mean efficacy measurements
(cough VAS score or LCQ scores), safety tests (AST, ALT, ALP, TB, GGT, BUN, creatinine,
sodium or potassium levels), and biomarkers will be analyzed using the same statistical
methods. Associations between the MMDT responders and non-responders with regard to
each identified pattern will be estimated using a logistic regression model, which
will be adjusted for covariates. All data will be analyzed using SPSSâ„¢ for Windows
software. The level of significance will be set at a two-sided P value of 0.05.

We, along with a professional statistician, will perform the data analysis for the
results.