Efficacy and Safety of YJP-40 in Patients with Acute Bronchitis: A Randomized, Double-Blind, Parallel Group Study
Article information
Abstract
Background
Pelargonium sidoides has been known to be effective in treating respiratory diseases. P. sidoides extract (Umckamin®, Han Wha Pharmaceuticals) was approved in Korea for acute bronchitis. YJP-40 (Umckamin plus®) is formulated with extract of P. sidoides and ivy leaf. Ivy leaf extract has an expectorant effect and has been used to treat bronchitis. The aim of this study was to compare the efficacy of YJP-40 syrup with Umckamin® syrup in patients with acute bronchitis.
Methods
This was a multicenter, randomized, double-blind, active-controlled, non-inferiority, phase III clinical trial. Patients were randomized 1:1 to either the test (YJP-40) or the control (Umckamin®) group. The primary endpoint was the change in bronchitis severity score (BSS) total score 7 days after administration.
Results
A total of 240 subjects (test group 121; control group 119) from seven hospitals were enrolled in this clinical trial. The average change in BSS total score 7 days after administration compared to before was –4.31±2.09 and –4.36±1.71 in the test group and the control group, respectively. The non-inferiority of the test group to the control group was demonstrated. The response rate at 7 days after administration was 87.16% (95/109) in the test group and 86.92% (93/107) in the control group (p=0.9778). There was no statistically significant difference between the groups in the incidence of adverse events.
Conclusion
YJP-40 can be a safe and effective treatment option for acute bronchitis.
Introduction
Acute bronchitis is one of the common causes of cough [1]. It is a self-remitting disease, however, the symptoms of acute bronchitis typically persist for approximately 3 weeks [2]. Treatment of acute bronchitis is mainly focused on symptom management [1]. Appropriate treatment can relieve the symptoms and shorten the duration.
Pelargonium sidoides extract (Umckamin®) was developed by Dr. Willmar Schwabe (Karlsruhe, Germany) and introduced to Korea by Han Wha Pharmaceuticals was approved by the Korean Ministry of Food and Drug Safety in 2010 for acute bronchitis.
YJP-40 (Umckamin plus®) syrup was developed by a South Korean pharmaceutical company (Han Wha Pharmaceuticals Co., Ltd., Seoul, Korea) and formulated with 11% ethanol extract of P. sidoides and 30% ethanol dried extract of ivy leaf. This medication was developed for acute bronchitis. P. sidoides is known to be effective in treating respiratory diseases. Ivy (Hedera helix) is a plant and ivy leaf (Hedera folium) extract has an expectorant effect and has been used to treat bronchitis.
Combining these two extracts are expected to provide complementary benefits. P. sidoides modulates the immune response and reduces inflammation. Ivy leaf extract targets mucus production and clearance. Together, they help relieve more symptoms and treat the main causes of respiratory problems more effectively. Moreover, there is increasing consumer demand for natural, plant-based medications to synthetic pharmaceuticals. Both P. sidoides and ivy leaf extracts have safer side-effect profile compared to conventional drugs. This advantage appeals for long-term use or use in children and fragile populations
There has been no clinical trial assessing the efficacy and safety of YJP-40 in patients with acute bronchitis. The aim of this study was to compare the efficacy of YJP-40 (Umckamin plus®) syrup with Umckamin® syrup in patients with acute bronchitis.
Materials and Methods
1. Study design
This was a multicenter, randomized, double-blind, active- controlled, non-inferiority, and phase III clinical trial. The enrollment criteria included (1) patients with acute bronchitis who had cough and sputum that developed within 48 hours; (2) ages between 1 and 64; and (3) a total score of bronchitis severity score (BSS) greater than or equal to 5. The exclusion criteria included (1) severe respiratory diseases such as bronchiectasis, lung cancer, interstitial lung disease, pneumonia, active tuberculosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma; (2) patients with active infection that required antibiotics treatment, and (3) patients with liver dysfunction, kidney dysfunction, active peptic ulcer, gastrointestinal bleeding, coagulation disorder, or malignancy. The following medications were not allowed within 2 weeks of enrollment and until the end of study: antibiotics, antiviral medications, angiotensin converting enzyme inhibitors, systemic glucocorticoids, inhaled corticosteroids, angiotensin receptor blockers, mucolytics, expectorants, and anti-cough medications.
Patients were randomized 1:1 to either the test (YJP-40) or the control (Umckamin®) group. The randomization table was generated by an independent statistician. SAS version 9.3 (SAS Institute, Cary, NC, USA) was utilized to create a randomization table with a stratified block randomization method at each center. The dosage of medication was 3 mL three times a day for children aged 1 and 5, 6 mL for ages 6 and 11, and 9 mL for ages 12 and above. The treatment period was 1 week. The efficacy and safety were assessed 7 days after administration. However, for subjects whose symptoms completely disappeared before 7 days, the last visit was allowed at that time. Among the tests for safety assessment, the electrocardiogram (ECG) test could be omitted at the discretion of the investigator for infants aged 1 to 2 years. In cases where the ECG test was omitted, an additional telephone survey was conducted 14 days after administration to monitor adverse events (Figure 1).
The study design.
The primary endpoint was the change in BSS total score 7 days after administration. The secondary endpoints were (1) change in BSS symptom scores at 7 days after administration; (2) response rate at 7 days after administration (BSS total score ≤3 or decrease of 7 points or more); (3) overall improvement evaluated by the investigator and the subject at 7 days after administration; (4) treatment effectiveness (completely recovered or significantly improved); and (5) overall satisfaction evaluated by the subject at 7 days after administration. Safety was evaluated by reporting adverse events, laboratory tests, vital signs, and ECG.
This study was approved by the Institutional Review Board (IRB) of Seoul St. Mary’s Hospital (KC16MDMT0651), and written informed consent was obtained from all patients or their next of kin.
2. Statistical analysis
To prove the non-inferiority of the test group to the control group, the 97.5% one-sided confidence interval (CI) (upper limit of the 95% two-sided CI) for the mean difference (test group-control group) in the change in the BSS total score at 7 days after administration compared to before administration was calculated. If the 97.5% one-sided CI (upper limit of the 95% two-sided CI) was less than 1.015, which was the non-inferiority margin, it was judged that the non-inferiority of the test group to the control group was met. The significance level was 0.025 (one-sided test), the power was 80%, and the minimum number of subjects for 1:1 allocation was calculated to be 104. Considering a 13% dropout rate, a total of 240 subjects were recruited, 120 per group. However, the sample size was not particularly calculated considering the number of pediatric patients. Analysis of covariance (ANCOVA) with the stratification factor (under/over 19 years of age) as a covariate was utilized. Data were expressed as number (%) or mean±-standard deviation. The adjusted results of ANCOVA were expressed as least square mean±standard error.
Results
1. Baseline characteristics
A total of 240 subjects (test group 121, control group 119) from seven hospitals (Wonkwang University Sanbon Hospital, Hallym University Kangnam Sacred Heart Hospital, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul National University Bundang Hospital, Nowon Eulji Medical Center, Eulji University, Seoul Medical Center, and Kyung Hee University Hospital at Gangdong) were enrolled in this clinical trial. Of the enrolled subjects, 12 subjects (test group 7, control group 5) dropped out due to withdrawal of consent, adverse reactions, or other reasons. Excluding these subjects, 228 subjects (test group 114, control group 114) completed the clinical trial. There were five and seven cases of major violations of the protocol in test and control groups, respectively (Figure 2).
Flow diagram of the study.
The mean ages of the test group and the control group were 33.80±12.72 years and 33.87±11.10 years, respectively, and the proportion of female subjects was 60.53% (69/114) and 59.65% (68/114), respectively. The proportion of pediatric patients was small. The number of patients aged less than 19 was five in test group and three in control group. The proportion of subjects by smoking status was described in Table 1. The average duration of cough onset was 2.39±0.54 days in the test group and 2.41±0.53 days in the control group, and the average duration of sputum onset was 2.36±0.57 days in the test group and 2.37±0.54 days in the control group.
Baseline characteristics
2. Primary endpoint
Mean BSS score decreased after the treatment in both groups (Figure 3). As a result of the per protocol set (PPS) analysis, the average change in BSS total score 7 days after administration compared to before was –4.31±2.09 and –4.36±1.71 in the test group and the control group, respectively. In the ANCOVA with the stratification factor (under/over 19 years of age) as a covariate, the average change in BSS was –4.49±0.39 and –4.55±0.39. The difference in change between the groups was 0.0560 (95% two-sided CI, – 0.4579 to 0.5698). The upper limit of the 95% CI (i.e., the upper limit of the one-sided 97.5% CI) was less than the non-inferiority margin of 1.015, demonstrating the non-inferiority of the test group to the control group. In the full analysis set (FAS), the results were similar (Table 2). The non-inferiority of the test drug was also met.
The changes of bronchitis severity score (BSS) before and after the medication. There was no significant difference in the changes of the BSS between two groups.
Changes in total BSS score
3. Secondary endpoints
In PPS, when the stratification factor (under/over 19 years of age) was adjusted as a covariate, the change in the cough score at 7 days after administration compared to before was –1.62±0.17 and –1.82±0.18 in the test group and the control group, respectively (p=0.0909). The change in sputum score was –1.50±0.19 and –1.58±0.19 (p=0.5151). Crackle was –0.44±0.13 and –0.42±0.13 (p=0.8167). Chest pain when coughing was –0.70±0.13 and –0.61±0.14 (p=0.3198). Dyspnea was –0.24±0.10 and –0.12±0.10 (p=0.0831). The results were similar in the FAS analysis.
The response rate at 7 days after administration was 87.16% (95/109) in the test group and 86.92% (93/107) in the control group. The odds ratio (OR) (test group/control group) was 1.01 (95% CI, 0.46 to 2.21), and there was no statistically significant difference between the groups (p=0.9778). Both groups showed excellent therapeutic effects with treatment response rates exceeding 85%. The scores for overall improvement assessed by the investigator at 7 days were 4.07±0.16 and 4.17±0.16 in the test and the control group, respectively (p=0.3275). The score assessed by the subjects was 3.49±0.17 and 3.71±0.17 (p=0.0704). The treatment effectiveness rate as assessed by the investigator for the test group was 76.15% (83/109) and for the control group was 76.64% (82/107). The OR was 0.97 (95% CI, 0.52 to 1.82; p=0.9211). The effectiveness rate as assessed by the subjects was 59.63% (65/109) and 71.96% (77/107). The OR was 0.58 (95% CI, 0.33 to 1.02; p=0.0605). The overall satisfaction evaluated by the subjects in the test group was 42.20% (46/109) for ‘very satisfied’ and 42.20% (46/109) for ‘satisfied.’ In the control group, 45.79% (49/107) were ‘very satisfied’ and 44.86% (48/107) were ‘satisfied’ (p=0.3803). The results were similar in the FAS analysis.
4. Safety
The subjects in the test group took YJP-40 an average of 17.98±4.14 times, and the control group took Umckamin ® an average of 18.22±3.46 times, and there was no statistically significant difference between the two groups (p=0.6224). The incidence of treatment emergent adverse events (TEAEs) was 18.18% (22/121 patients, 26 cases) in the test group and 11.76% (14/119 patients, 17 cases) in the control group (Table 3). The incidence of adverse drug reactions (ADRs) was 11.57% (14/121 patients, 17 cases) in the test group and 6.72% (8/119 patients, 11 cases) in the control group. There was no statistically significant difference between the groups in the incidence of TEAEs and ADRs. There was no serious adverse event (SAE) in either group.
Treatment emergent adverse events
Discussion
Acute bronchitis affects approximately 5% of adults annually and about 10 outpatient visits per 1,000 people occur due to acute bronchitis [3]. Acute bronchitis is an inflammatory response caused by infection of bronchial epithelial cells, with cough as the main symptom, and sputum may be produced as the disease progresses. In addition, acute bronchitis can cause temporary airway obstruction or bronchial hyperresponsiveness due to a complex combination of mucosal damage and inflammatory mediators, and may result in a decline in lung function.
Acute bronchitis is generally mild and self-limiting, but data on long-term outcomes are limited [4]. A study of 653 adults with acute lower respiratory tract infection symptoms found that 20% revisited their doctor within a month due to persistent or recurrent symptoms, primarily cough [5]. Another large study involving 2,061 adults with acute cough or likely lower respiratory tract infection (excluding pneumonia) found that 18% experienced symptom deterioration, leading to re-consultation. However, only three individuals required hospitalization [6]. These studies highlight short-term symptom recurrence and deterioration but suggest severe outcomes are rare.
The root extract of P. sidoides has been commonly used for the treatment of respiratory diseases. Nonclinical studies have shown that EPs 7630, a aqueous-ethanolic extract of P. sidoides roots antimicrobial and immunomodulatory properties [7]. An in vitro study further showed that it has an antiviral effect [8]. A meta-analysis demonstrated that EPs 7630 is effective for the treatment of acute bronchitis and acute rhinosinusitis [9]. In addition, Matthys et al. [10] showed that EPs 7630 as addon, prolonged the time to acute exacerbation in patients with COPD and reduced exacerbations frequency in a randomized, double-blind, placebo-controlled trial.
The extract of ivy leaf is registered as an expectorant in patients with respiratory diseases associated with a productive cough. In a systematic review, ivy leaf preparations were effective and safe for use in the treatment of cough due to upper respiratory infections and bronchitis [11]. Zeil et al. [12] showed that additional treatment with ivy leaf extract improved lung function in children with asthma. An in vitro study showed that EA 575® (ivy leaves dry extract) has anti-inflammatory effects via regulation of the nuclear factor kB pathway [13].
The combination of these two effective components is expected to be effective for acute bronchitis. The extract of P. sidoides is already approved in South Korea for acute bronchitis. The extract of ivy leaf is also approved and used widely. In clinical practice, these two components are sometimes prescribed simultaneously to one patient. YJP-40 syrup, a combination of the two extracts, was developed to improve the compliance and provide convenience. However, there has been no clinical trial to prove the efficacy. To the best of our knowledge, this is the first clinical trial that demostrates the efficacy and safety of a combined formula of extracts of P. sidoides and ivy leaf. YJP-40 demonstrated its non-inferiority when compared to Umckamin® in patients with acute bronchitis. There was no serious ADR.
There are limitations in this study. First, there was no placebo group in this study. Thus, the efficacy of YJP-40 was only indirectly proven. However, Umckamin® is a well-known effective medication for acute bronchitis and is already proven in South Korea. Also, other medications for acute bronchitis have demonstrated efficacy by proving non-inferiority to Umckamin® syrup. For example, Kim et al. [14] conducted a phase III trial comparing HL301 with Umckamin® in patients with acute bronchitis. The changes in BSS were not different between HL301 and Umckamin® [14]. HL301 demonstrated its superiority compared to placebo in previous phase II trials [15,16]. Thus, we assume that YJP-40 is also effective in patients with acute bronchitis. Second, the effect of YJP-40 was not superior to Umckamin®. Since this was a non-inferiority study, it is not possible to prove superiority of the YJP-40. However, there was no sign of better efficacy of YJP-40 than Umckamin®. YJP-40 is a combination drug composed of exacts of P. sidoides and ivy leaf. However, the efficacy was comparable to that of a single agent. This may be because acute bronchitis is a self-remitting disease and a single agent is already sufficient for treatment. Further study regarding the efficacy of YJP-40 in other respiratory diseases such as chronic bronchitis, asthma, and COPD is needed. Another potential reason is that If both extracts act through similar pathways, their combined use may not provide additional benefits compared to a single extract. Thus, further research, including a placebo control group, should be necessary in the future to assess the superiority of a combination drug. Third, the number of pediatric patients was very small. Thus, it is difficult to draw the same conclusion about the efficacy and safety of YJP-40 in this age group (age less than 19). Further clinical trial for these patients is needed.
In conclusion, the efficacy of YJP-40 was not inferior to that of Umckamin® in patients with acute bronchitis. The incidence of adverse events was also comparable. YJP-40 was well tolerated and there was no SAE. YJP-40 can be a safe and effective treatment option for acute bronchitis.
Notes
Conflicts of Interest
Chin Kook Rhee received consulting/lecture fees from MSD, AstraZeneca, GSK, Novartis, Takeda, Mundipharma, Boehringer-Ingelheim, Sanofi, Bayer, Organon, Roche, Teva-Handok, Kolon, Yuhan, Ahngook, Chong Kun Dang, Dong Wha, Daewon, Boryung, Han Wha, and Hanlim. Han Wha Pharmaceuticals did not provide any financial support for this manuscript. Han Wha Pharmaceuticals had no role in writing this manuscript.
Chin Kook Rhee is a deputy editor of the journal, but he was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Funding
No funding to declare.