Acute bronchitis is defined as an acute lower respiratory tract infection disease characterized by cough with or without sputum, lasting no more than 3 weeks with no clinical or any recent radiographic evidence to suggest an alternative explanation (Smith et al., 2020). The diagnosis of acute bronchitis requires an assessment to differentiate from pneumonia, asthma as there are no specific diagnostic criteria, and a symptom scoring system is used clinically to evaluate severity. (Albert, 2010). Acute bronchitis is a common clinical disease responsible for both primary care clinicians and emergency department attendances (Woodhead et al., 2011). It is reported in up to 10% of the population, with approximately 100 million ambulatory visits per year in the United States (Grijalva et al., 2009). In South Korea, acute bronchitis is also the second most frequent outpatient department (OPD) disease, which is visited by 16 million patients and places a substantial economic burden on the public health system (Sun-min Kim, 2020). Acute exacerbation of chronic bronchitis (AECB) is another common disease with cough and sputum as the main symptoms. The overall rate of AECB episodes was reported to be up to 3% and increased between 1992 and 2000 (Feeney et al., 2004).

Acute bronchitis is mainly caused by a viral infection and less than 10% of bacterial infections; therefore, antibiotics do not have benefits in viral bronchitis (Braman, 2006). In addition, antibiotics have side effects on normal bacteria, resistance to respiratory pathogens, and cost of antibiotic treatment; however, the overall antibiotic prescription rate for acute bronchitis was 60–83% (Smith et al., 2017). In addition, in AECB, because 30% of AECB results from viruses and 20% of AECB are due to non-infectious causes, judicious use of antibiotics is recommended for differentiating between bacterial, and non-bacterial infections (Fendrick et al., 2001). Patients with cough/sputum for acute bronchitis and mild AECB are usually prescribed antitussives, expectorants, beta-2 agonists, and alternative therapies as symptomatic treatments. However, central antitussives have limited efficacy for bronchitis, and expectorants, such as mucolytic agents, and have no consistent favorable effects in several trials. As beta-2 agonist bronchodilators may be useful for wheezing accompanying cough, it should not be routinely used to alleviate cough due to its side effects (Braman, 2006). As alternative therapies, ivy leaf extracts are used in various European countries, and several trials have been conducted on Chinese medicinal herbs for acute bronchitis, but there is insufficient evidence to support its use (Holzinger and Chenot, 2010; Jiang et al., 2012).

In this study, we evaluated the efficacy and safety of a combined formulation GHX02, containing four herbs that have been clinically used for bronchitis at Daejeon Korean Medicine Hospital, Daejeon University. GHX02 originated from gwaruhaengryeon-hwan in Dong-Ui-Bo-Gam, the classical medical text approved by UNESCO in 2009. Gwaruhaengryeon-hwan is composed of three herbs (Trichosanthis semen, Armeniacae semen, and Coptidis rhizoma) known to stabilize lung-heat (肺熱), usually meaning inflammation and acute stage of the disease in syndrome differentiation of traditional oriental medicine. Here, we tried to expand the effect by adding a herb (Scutellariae radix) with a similar therapeutic mechanism. Gwaruhaengryeon-hwan demonstrated its anti-inflammatory effects on COPD and particulate matter-induced lung injury in a mouse model (Lee et al., 2017). Scutellariae radix has also been reported to inhibit the production of several inflammatory cytokines (Kim et al., 2015) and have antioxidant effects (Guo et al., 2013). Moreover, a series of preclinical studies showed that GHX02 reduced airway inflammation, sputum production, cough, suppressed PM10D-induced inflammatory symptoms in the lung (Yang et al., 2020), and had an anti-COPD effect (Yang et al., 2018). Additionally, the safety of GHX02 has been verified in the assessment of 4-weeks repeated-dose oral toxicity and genotoxicity (Ji et al., 2020). Although there are many animal studies and clinical experiences, there have been no clinical trials in humans that evaluate GHX02. Therefore, we planned a phase II, randomized, double-blind, placebo-controlled, multicenter trial to determine the efficacy and safety of GHX02 compared with placebo, and find a suitable dosage of GHX02 for the treatment of bronchitis. This study is expected to provide clinical data for the following phase III trials.

The study protocol was approved by the Institutional Review Board (IRB) at each center (IRB number: DJDSKH-17-DR-14 at Daejeon Korean Medicine Hospital, KOMCIRB 2018-10-007-001 at Kyung Hee University Korean Medicine Hospital, and 2018010 at Pusan National University Korean Medicine Hospital). In contrast to the previously published protocol (Lyu et al., 2018), this study included patients with AECB with symptoms similar to those with acute bronchitis but excluded those who required glucocorticoids or antibiotic treatment. Accordingly, stratified block randomization was not conducted for Korean pattern identification, but as acute bronchitis and AECB.

Both acute bronchitis and AECB have cough and sputum as the main symptoms, and the prevalence is high enough to be common in primary care and is also increasing due to air pollution such as particulate matter (Kampa and Castanas, 2008). Consequently, the demand for antitussives and expectorants increases, but the evidence on the appropriateness of antibiotic prescriptions and the effect of symptomatic treatment for bronchitis is unclear. In particular, the excessive use of antibiotics for acute bronchitis, which is mostly caused by viruses, only leads to increased resistance strains of common organisms, adverse effects on normal bacteria colonizing the intestine, such as gastrointestinal symptoms, and medical costs (Smith et al., 2017). Antitussives and expectorants for symptomatic treatment also have adverse effects on the central nervous system, such as respiratory depression, nausea, dizziness, and uncertain effectiveness (Bolser, 2006). Therefore, we conducted this clinical trial to establish the basis for an effective bronchitis treatment using herbal medicines with fewer adverse effects that contribute to the reduction of the medical cost burden.

GHX02, which contains four herbs, is a combined formulation that has been clinically used for bronchitis at Daejeon Korean Medicine Hospital, and Daejeon University. In preclinical studies, GHX02 decreased the frequency of coughing and exhibited expectorant activity and antimicrobial activity against Streptococcus pneumoniae in a mouse model. GHX02 also suppressed histamine release from mast cells and reduced leukocyte levels, prostaglandin E2 (PGE2), interleukin (IL)-4, and IL-13. Furthermore, GHX02 suppressed PM₁₀D-induced inflammatory symptoms in the lungs, such as increased alveolar wall thickness, cytokine release, and collagen fiber accumulation (Yang et al., 2020). In addition, we observed that GHX02 efficiently inhibited airway inflammation by inhibiting the expression of proinflammatory cytokines and the migration of inflammatory cells in a COPD-induced mouse model (Yang et al., 2018). In a subsequent study investigating the mechanism, the GHX02 herbal formula protects against TNF-α-induced inflammation in human bronchial epithelial cells by blocking NF-κB and activating the Nrf-2/HO-1 pathway.

In this study, which is the first human clinical trial of GHX02, we evaluated the efficacy and safety of GHX02 for the treatment of acute bronchitis and AECB in a randomized, double-blind, dose-finding phase II, placebo-controlled, multicenter trial. The primary outcome measure in this study was the BSS, which was evaluated based on the patient’s subjective symptoms. Two different doses of GHX02 (1920 mg/day, 960 mg/day) were effective in decreasing the BSS from baseline to 7-days treatment compared to placebo. The mean difference in the BSS was 4.2 ± 2.0 in the high-dose GHX02 group, 4.5 ± 1.8 in the standard-dose GHX02 group, and 3.8 ± 2.1 in the placebo group (Figure 2). These results are consistent with those of previous studies that used herbal medicines (Kamin et al., 2010; Park et al., 2017). Considering that the BSS is used to diagnose acute bronchitis with 5 points more and is a valid clinical measure for acute bronchitis treatment (Matthys and Kamin, 2013), the results of this study can be judged as a clinically significant improvement. In secondary outcome measures, IMPSS, which evaluates patient satisfaction after treatment, and showed a statistically significant difference between the groups. The IMPSS on Day 7 was 2.0 ± 0.7 in the standard-dose GHX02 group and 2.5 ± 0.6 in the placebo group. These results were in line with those of other clinical trials that used BSS as the primary outcome measure and IMPSS as the secondary outcome measure (Kardos et al., 2014). As the BSS has subjective components, there may be individual variations. However, the BSS is supported by the results of additional outcome measures, such as IMPSS, which focus on general outcomes and patient satisfaction with the treatment (Matthys and Kamin, 2013). In addition, the frequency of coughing fits gradually decreased over 7 days in all groups, and the mean differences from baseline to Day 7 were statistically significant between the standard-dose GHX02 and the placebo groups. The frequency of coughing fits is an objective indicator of the main symptoms of bronchitis, and its change means that the treatment group showed improved clinical symptoms compared to the placebo group.

In the other outcome measures, there were no statistically significant differences between the groups, but the high-dose GHX02, and standard-dose GHX02 groups showed more clinical improvement than the placebo group. The QCSCS that evaluates cough, sputum, daily living, and sleeping was not reported for its minimum clinically important difference (MCID) but decreased by half in the order of high-dose GHX02, standard-dose GHX02, and placebo groups. In the LCQ, which is the most frequently used questionnaire for QOL related to cough, the MCID was reported as 2–2.5 points (Lee et al., 2013; Kardos et al., 2014). Therefore, the results of this study are clinically significant in that the LCQ showed a change of 3.9 ± 3.2 points in the high-dose GHX02 group and 3.3 ± 2.3 in the standard-dose GHX02 group. The IMOS was better in the order of high-dose GHX02, standard-dose GHX02, and placebo groups. Since cough affects not only the physical aspect but also the psychological and social life, it is necessary to comprehensively evaluate all parts to measure the degree of cough (Brignall et al., 2008). In this study, we evaluated both objective and subjective aspects of symptoms using several outcome measures. The BSS, which is based on the investigator’s objective clinical evaluation in combination with the subjective feedback of the patient, showed significant improvement as the primary outcome measure. Although there were clinical improvements, IMPSS and the frequency of coughing fits in objective or subjective secondary outcome measures did not show statistically significant differences between the groups. These effects in the placebo group may be due to the placebo effect, and to evaluate the efficacy of GHX02 more accurately, further trials should be conducted.

In terms of safety, there were no serious AEs in this study, and several mild AEs were not clinically significant. The vital signs and laboratory examinations assessed before and after taking the GHX02 did not change significantly between the groups. Both preclinical and clinical trials have indicated that GHX02 is safe during the drug-taking period.

This study has several limitations. First, we stratified block randomization into acute bronchitis and AECB, but in the AECB subgroup, and the number of subjects was not enough to compare the differences between the groups. In this trial, the number of patients with acute bronchitis was 104, while the total number of patients with AECB was 13. Since only the efficacy for acute bronchitis was confirmed, and for AECB was not confirmed, future studies targeting AECB may be independently conducted. Second, only adults were involved in this study; children were excluded because clinical drugs are recommended to be first applied to adults. However, the prevalence of bronchitis is high in children, and the adverse effects of central antitussives, such as codeine, are more severe in children (Malesker et al., 2017). Therefore, further trials targeting children need to be conducted. Third, BSS is used to diagnose and evaluate the impact of treatment in clinical trials for acute bronchitis, but it would be beneficial if a biomarker was developed additionally. BSS and other questionnaires can also evaluate acute bronchitis as a validation tool, but developing biomarkers will provide more objective evidence.

Despite these limitations, this is a meaningful study that raises the possibility of generalization by creating scientific grounds for Korean medicine used in clinical practice. By comparing the two different doses of GHX02, the most effective dose was considered 960 mg/day. In the next phase III study, it will be necessary to specify the target disease as acute bronchitis, which has been proven effective in this trial, and compare it with the active control group for sufficient evidence.

In conclusion, this study suggests that GHX02 has clinical improvements in patients with acute bronchitis and can be used as a safe and effective remedy for acute bronchitis. Our data will be used as clinical evidence to plan a phase III confirmatory clinical trial to evaluate the efficacy of GHX02 for acute bronchitis compared with an active control group.