Efficacy and safety of inhaled ambroxol hydrochloride solution in Chinese pediatric patients with acute lower respiratory tract infections: a real-world, multicenter, open-label, single-arm study

Introduction

Background

Acute lower respiratory tract infections (ALRTIs), caused by viral, bacterial, or mycoplasmal infections, are a leading cause of hospitalization and mortality in children worldwide (1,2). ALRTIs encompass acute pneumonia, acute bronchitis, asthmatic bronchitis, and bronchiolitis (3), and are characterized by cough, dyspnea, fever, and production of tenacious sputum (4). Due to their narrow respiratory tracts, delicate mucous membranes, weak cough reflexes, and poor ciliary movement, children are more susceptible to sputum retention (5). If not promptly managed, retained sputum can exacerbate infection, obstruct airflow, and result in a progressive decline in lung function (6). Therefore, appropriate expectorants are crucial for promoting sputum clearance and the clinical management of ALRTIs.

Ambroxol [2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl) benzylamine] is a synthetic derivative of vasicine, used as a mucolytic agent that has been shown to reduce viscid or excessive secretions in various respiratory diseases (7,8). It decreases sputum viscosity by stimulating the secretion of serous glands and inhibiting mucous gland secretion in the respiratory tract. Additionally, ambroxol breaks down mucopolysaccharide fibers and limits mucoprotein synthesis (9,10). Tamaoki et al. (11) demonstrated that ambroxol can selectively inhibit sodium ion (Na⁺) absorption by airway epithelial cells, thereby enhancing airway surface hydration. Furthermore, Saito et al. (12) found that ambroxol promotes airway ciliary beating via voltage-gated calcium ion (Ca²⁺) channels. Clinically, ambroxol is a first-line expectorant, administered at high doses via oral or intravenous routes (13). Notably, prior to the approval of ambroxol hydrochloride solution for inhalation (AHSI), ambroxol hydrochloride injection was widely used off-label for inhalation therapy in the management of respiratory diseases in China. Compared with systemic therapy, nebulized inhalation delivers drugs directly to the airways, achieving relatively high local drug concentrations to improve bioavailability (14), while requiring lower dosages and resulting in fewer adverse reactions (15).

Rationale and knowledge gap

The nebulized formulation—AHSI—was approved in China in 2019, and its efficacy has been demonstrated in a recent multicenter, randomized, double-blind, placebo-controlled phase III trial. In that trial, children with LRTI who received AHSI showed significantly greater reductions in cough and phlegm-sound scores compared with placebo, with a favorable safety profile (16).

However, such randomized controlled trials (RCTs) are conducted under highly standardized conditions: stringent eligibility criteria often exclude children with comorbidities, severe presentations, or concomitant therapies, and a single nebulizer device is typically mandated. Consequently, while RCTs establish efficacy under ideal circumstances, they cannot fully capture the variability of routine clinical practice, where patients are heterogeneous, treatment adherence differs, and multiple nebulizer brands and driving principles are used interchangeably. This distinction between efficacy and real-world effectiveness leaves critical gaps in the evidence base, particularly for clinicians who must make decisions for complex pediatric populations and select compatible devices for aerosol delivery.

Objective

We conducted this large-scale, multicenter, real-world study to evaluate the effectiveness, safety, and device compatibility of a 7-day AHSI regimen added to standard care in a broadly representative cohort of children hospitalized with ALRTI. By enrolling diverse patients, allowing routine concomitant medications, and assessing performance across nine commercially available nebulizer systems, the present study aimed to generate evidence that directly informs everyday clinical decision-making and to validate the practical applicability of AHSI as an expectorant therapy in pediatric respiratory care. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0178/rc).

Methods

Study design

This was an open-label, single-arm, multicenter clinical trial conducted across 62 medical centers in China from April 12, 2021, to April 20, 2022, with registration in the Chinese Clinical Trial Registry (registration number: ChiCTR2100043783). The trial aimed to evaluate the efficacy and safety of AHSI in pediatric patients with ALRTIs. This study was approved by the Institutional Review Boards of all participating institutions [Leading Medical Center: Beijing Children’s Hospital, Capital Medical University (No. [2020]-Y-016-C-01)], and adhered to the principles of the Declaration of Helsinki and its subsequent amendments, and Chinese Good Clinical Practice (GCP) guideline. Written informed consent was obtained from the legal guardians of all patients prior to the initiation of any study procedures.

Participants

Pediatric patients were eligible for enrollment if they met all the following inclusion criteria: (I) diagnosed with ALRTIs, including acute bronchitis (asthmatic bronchitis, bronchiolitis, and acute pneumonia); (II) presented with cough, tenacious sputum, and difficulty expectorating, with a cough score of ≥2 within the preceding 24 hours; (III) hospitalized and aged ≥6 months; (IV) duration of ALRTI symptoms <7 days; and (V) voluntary participation in the study, with written informed consent signed by legal guardians in compliance with good clinical practice (GCP) regulations.

The exclusion criteria were as follows: (I) diagnosed with upper respiratory tract infections; (II) diagnosed with severe pneumonia, bronchial asthma, or interstitial lung disease; (III) complicated with diseases associated with massive respiratory tract secretions, such as primary ciliary dyskinesia and bronchiectasis; (IV) complicated with disorders of the heart, brain, liver, kidney, blood, immune, or endocrine systems, skin diseases, congenital respiratory diseases, or malnutrition; (V) diagnosed with peptic ulcer; (VI) evidence of liver or kidney dysfunction [alanine aminotransferase (ALT) >1.5 times the upper limit of normal (ULN); total bilirubin (TBil) and serum creatinine (Scr) > ULN]; (VII) a history of atopy or known hypersensitivity to any component of the study drugs; (VIII) requirement for systemic antihistamines during the study period; (IX) current or past participation in other clinical trials within the previous 3 months; (X) suspected or confirmed history of drug abuse, or other diseases/conditions that may reduce enrollment feasibility or complicate participation, as judged by the investigator; (XI) poor compliance, precluding completion of the clinical study; and (XII) at the investigator’s discretion, deemed unsuitable for enrollment.

Treatment strategies

Pediatric patients received AHSI (Hanmi Pharm. Co., Ltd., Hwaseong-si, Korea; approval No. JX20180263) in combination with standard therapy for 7 consecutive days or until clinical recovery was achieved. Drug delivery was via nebulized inhalation, administered twice daily with a minimum 6-hour interval between doses. Dosage was adjusted based on age: 1 mL per dose for patients aged 6 months to 2 years, 2 mL per dose for those aged 2 to 12 years, and 3 mL per dose for patients aged ≥12 years. Clinical recovery was defined as the resolution of all ALRTI-related signs and symptoms, or a return to the pre-infection baseline status. Patients were discharged upon achieving clinical recovery, which was documented as a completed case.

To minimize inter-rater variability in the assessment of subjective endpoints such as cough scores, all investigators and research staff across the 62 centers underwent centralized, standardized training on the symptom scoring criteria (Table 1) prior to study initiation. Uniform case report forms were used for data collection, and regular monitoring visits were conducted throughout the trial to ensure consistent application of the assessment procedures and to reinforce protocol adherence.

Definitions

The primary efficacy endpoints of this study were the cough improvement rate and clinical response rate. The cough improvement rate was defined as a reduction of at least one grade in the cough score following treatment. The clinical response rate was evaluated based on cough severity, pharyngeal sputum, and lung auscultation findings. Symptom and sign severity were assessed using a 0–3 point scale and recorded at each study visit. A clinical response was defined as a ≥1-point reduction in the cough score if cough was the only symptom present at baseline. If two or more symptoms were present at baseline, a clinical response required a ≥1-point reduction in at least two of the assessed indicators. The score evaluation criteria are presented in Table 1 (17). The secondary efficacy endpoints included longitudinal changes in cough, pharyngeal sputum, and lung auscultation scores from day 0 to 7. Baseline cough scores and pharyngeal rale scores were assessed within 24 hours prior to study enrollment, while baseline pulmonary rale scores were determined by lung auscultation at the time of enrollment in pediatric participants. Exploratory analysis observation outcomes: The exploratory analysis was conducted to evaluate whether the brand and/or working principle of the nebulizer impacted clinical outcomes.

Safety observation outcomes: safety was evaluated based on the following indicators: (I) adverse events (AEs); (II) vital signs, including temperature, respiratory rate, heart rate, and blood pressure; (III) hematologic and urinary laboratory parameters: red blood cells, white blood cells, hemoglobin, platelets, urinary leukocytes, urinary erythrocytes, urinary protein, blood glucose, ALT, aspartate aminotransferase (AST), TBil, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), blood urea nitrogen (BUN), and creatinine (Scr); and (IV) 12-lead electrocardiogram (ECG) for participants aged ≥3 years.

Sample size

Sample size estimation based on safety endpoints: Previous clinical trials reported that the adverse reaction rate of AHSI was 2.56%, with adverse reactions mainly manifested as aggravated wheezing, skin allergic reactions, and digestive system abnormalities such as diarrhea. Meanwhile, according to reference (18), the adverse reaction rate of nebulized ambroxol hydrochloride injection was 1.45%.

This study aimed to observe adverse reactions with an incidence rate of no less than 0.15% for AHSI. The calculated sample size was 2,000 (3/0.0015) patients, which could basically meet the requirements for drug safety evaluation in this study. Considering subject dropout and case distribution across study centers, the sample size was expanded, and a total of 2,600 patients were enrolled in the present study.

Statistical analysis

All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Hypothesis testing adopted a two-sided test with a significance level of α=0.05. Continuous data were expressed as mean ± standard deviation (SD), with 95% confidence intervals (CIs) calculated. Categorical data were presented as frequencies and percentages. A P value <0.05 was considered statistically significant.

Baseline analysis was conducted using data from the full analysis set (FAS). Efficacy data were analyzed using both the FAS and per protocol set (PPS). The FAS included all randomized patients who received at least one dose of the study drug. The PPS comprised all randomized patients who met all inclusion criteria, completed the full course of study drug administration, and had no major protocol deviations. AEs and adverse reactions were analyzed using the safety set (SS), which included patients who received the study drug and had at least one safety evaluation record.

Missing data were imputed using the last observation carried forward (LOCF) method. Consistent with the observational design of the study, statistical analyses were primarily descriptive and exploratory; no adjustments for potential confounders or center effects were applied.

Results

Baseline characteristics of participants

This trial was conducted across 62 study centers. A total of 2,679 participants underwent screening, among whom 2,599 (100.00%) were successfully enrolled and included in the FAS. Three participants (0.12%) were excluded due to missing visit data and non-compliance with eligibility criteria. A total of 2,597 participants (99.88%) received the study medication and were included in the SS, of whom 2,502 (96.23%) completed the trial. Ninety-eight participants (3.77%) discontinued the trial during the study period. Additionally, 328 participants (12.62%) were excluded from the PPS due to reasons including non-compliance with eligibility criteria, use of prohibited medications, protocol-mandated visit window deviations, inadequate medication adherence, and fulfillment of exclusion criteria, resulting in a final PPS of 2,216 participants (85.52%). Figure 1 presents the participant disposition flowchart. The demographics and baseline characteristics of patients are presented in Table 2.

Figure 1 The flowchart of the subjects distribution. FAS, full analysis set; PPS, per protocol set; SS, safety set.

Efficacy analysis

Primary efficacy outcome

Among the 2,599 participants included in the FAS, the cough improvement rate was 96.73% with a 95% CI of (96.05%, 97.41%), and the clinical response rate was 94.73% with a 95% CI of (93.87%, 95.59%). For the 2,216 participants in the PPS, the cough improvement rate was 99.05% (95% CI: 98.65%, 99.46%) and the clinical response rate was 97.07% (95% CI: 96.36%, 97.77%). Consistent results were obtained from the analyses of the PPS and FAS. Results are presented in Table 3.

Secondary efficacy outcomes

Regarding secondary efficacy endpoints, both FAS and PPS analyses demonstrated a statistically significant reduction in cough scores over time. In the FAS, the baseline cough score was 2.10, which decreased to 0.77 on day 7 of medication, representing a mean reduction of 1.33 (95% CI: 1.31–1.35). This reduction was statistically significant compared with baseline (P<0.01), as presented in Figure 2A. Cough scores in both the FAS and PPS showed a progressive downward trend with increasing medication duration, indicating gradual improvement in cough symptoms throughout the treatment course (Figure 2B).

Figure 2 Diachronic changes of (A,B) cough score, (C,D) throat sputum score, and (E,F) lung auscultation score. CI, confidence interval.

Consistent trends were observed for pharyngeal sputum scores and pulmonary auscultation scores, as presented in Figure 2C-2F. From baseline to day 7, the pharyngeal sputum score decreased significantly from 1.65 to 0.23 (P<0.001; Figure 2C), with a mean reduction of 1.42 (95% CI: 1.39–1.45). As shown in Figure 2D, the pharyngeal sputum score also declined gradually with treatment progression. Similarly, the pulmonary auscultation score exhibited a statistically significant decrease from baseline to day 7 (from 1.44 to 0.20; P<0.001). Additionally, in both FAS and PPS analyses, the improvement rate of pharyngeal rale scores exceeded 90%, and the improvement rate of pulmonary auscultation scores exceeded 83%, as presented in Table 3.

Exploratory analysis observation outcomes: subgroup analyses by nebulizer device

As the delivery of nebulized inhalation therapy is device-dependent, we investigated the potential impact of nebulizer brand and driving principle on the efficacy of AHSI. Subgroup analyses encompassed nine commercially available nebulizer brands (e.g., PARI, OMRON, Bairui Medical) and two driving principles (compressed air, compressed oxygen).

Within the FAS, no statistically significant differences were observed across the nine nebulizer brands for either cough improvement rate (range, 89.89–100.00%) or clinical response rate (range, 89.89–100.00%) (cough improvement: χ²=4.21, P=0.86; clinical response: χ²=3.95, P=0.88). In the PPS, both cough improvement and clinical response rates exceeded 94% for all brands, with no significant inter-group differences (cough improvement: χ²=3.87, P=0.87; clinical response: χ²=2.98, P=0.91). High efficacy was consistently observed with mainstream brands (PARI, OMRON, Bairui Medical), all achieving cough improvement rates >97%, confirming the good compatibility of AHSI with commonly used clinical nebulizers.

Efficacy endpoints were comparable between compressed air and compressed oxygen-driven nebulizers. No statistically significant differences were detected in cough improvement rate or clinical response rate in either the FAS or PPS (Table 4). Minor numerical variations in secondary endpoints at individual follow-up visits lacked clinical relevance.

These results confirm that AHSI’s clinical efficacy is independent of nebulizer brand or driving principle under standardized operation, providing critical evidence for flexible nebulizer selection in clinical practice and enhancing the generalizability and accessibility of AHSI for pediatric ALRTI.

Safety

Analysis of overall medication use in the FAS revealed that the median total exposure time to the study drug was 4.62±1.50 days, with a mean total dosage of 14.85±6.62 mL. Based on the SS, 2,483 participants (95.50%) had an adherence rate ranging from 80% to 120%, while 117 participants (4.50%) had an adherence rate of <80% or >120%. Overall, the participants demonstrated good adherence to the study medication.

Safety analysis of AHSI was conducted, with results presented in Table 5. A total of 286 AEs were reported in 286 participants (11.02%) throughout the trial. Among these, 3 events (0.12%) were classified as SAEs, and 12 events (0.46%) led to treatment discontinuation. Further analysis showed that 10 participants (0.39%) experienced mild or moderate drug-related AEs (DRAEs), including: 4 cases (0.15%) of rash (3 resolved after AHSI discontinuation and treatment, 1 resolved spontaneously without any intervention); 2 cases (0.08%) of abnormal liver enzyme levels (1 case with ALT 102 IU/L and AST 130 IU/L, which resolved after AHSI discontinuation and hospitalization; 1 case with ALT 81.03 U/L and AST 65 U/L, which resolved spontaneously without any intervention); 2 cases (0.08%) of nausea and vomiting (both resolved spontaneously without any intervention); 1 case (0.04%) of diarrhea (resolved with treatment); and 1 case (0.04%) of epistaxis (resolved after temporary suspension of AHSI). No serious DRAEs were reported during the trial.

In addition, vital signs of pediatric participants, including body temperature, heart rate, and respiratory rate, remained stable throughout the study period.

Discussion

Key study findings

This large-scale, multicenter, prospective real-world study evaluated the efficacy and safety of a 7-day course of AHSI in Chinese pediatric patients with ALRTI. Treatment with AHSI led to significant improvement in core respiratory symptoms, including cough, throat rales, and abnormal pulmonary auscultation findings. Within the FAS, the cough improvement rate was 96.73% and the clinical response rate was 94.73%, with even more pronounced outcomes observed in the PPS. All secondary efficacy endpoints—scores for cough, throat rales, and pulmonary auscultation—demonstrated significant reductions throughout the treatment period (all P<0.001). Regarding safety, the incidence of DRAEs was low (0.39%). Reported events were primarily mild to moderate in severity and included skin rashes, abnormal liver enzyme levels, and gastrointestinal reactions. No serious DRAEs were reported, confirming the favorable tolerability profile of AHSI in this pediatric population.

Consistency of efficacy and safety: subgroup analyses by disease subtype

To assess the generalizability of AHSI’s effects across ALRTI subtypes, subgroup analyses were performed for pneumonia and bronchitis. In the pneumonia subgroup (n=2,076), the cough improvement and clinical response rates were 96.87% and 94.99%, respectively (19). Corresponding rates in the bronchitis subgroup (n=491) were 96.33% and 93.69% (17). No statistically significant differences were observed for these primary endpoints between either subgroup and the overall study population (cough improvement: 96.73%; clinical response: 94.73%; all P>0.05). DRAE incidence remained very low in both subgroups (0.43% for pneumonia, 0.20% for bronchitis). These findings collectively indicate that the efficacy of AHSI in alleviating core respiratory symptoms is consistent across ALRTI subtypes, accompanied by a uniformly favorable safety profile in children with either pneumonia or bronchitis.

Furthermore, no significant differences were detected in cough improvement rate (100% vs. 95.88%, χ²=1.29, P=0.256), clinical response rate (96.30% vs. 93.36%, χ²=0.29, P=0.59), or DRAE incidence between patients with and without a history of allergy. This suggests that AHSI is equally effective and safe for atopic children, and no adjustment to the treatment regimen is necessary based on ALRTI subtype or allergic history.

External validation: comparison with a phase III RCT

The core findings of this study align closely with those from a previously published randomized, double-blind, placebo-controlled phase III RCT (ChiCTR2300072466) (16), thereby establishing a complementary evidence chain integrating real-world data with rigorously controlled trial results (Table 6). It is noteworthy that the present study employed a single-arm, open-label design involving a population that closely reflects real-world clinical practice, including patients on concomitant medications and with varying baseline health statuses. In contrast, the phase III RCT utilized a placebo control to account for natural disease progression and placebo effects. Together, these complementary study designs reinforce the validity and reliability of the efficacy and safety data for AHSI in pediatric ALRTI.

Study strengths and limitations

Strengths

First, the study featured a large-sample, multicenter design, and enrolling 2,599 pediatric patients across 62 medical centers nationwide. This broad inclusion of diverse geographic regions, ethnicities, and ALRTI subtypes strengthens the external validity of the findings. Second, comprehensive subgroup analyses—stratified by disease subtype, allergic history, and nebulizer device—systematically verified the generalizability and device compatibility of AHSI within real-world pediatric practice. Third, by including patients on concomitant medications and allowing varied device use, this real-world study addresses evidence gaps often present in Phase III RCTs, which typically employ stricter protocols. Consequently, the findings more accurately reflect the actual clinical application of AHSI.

Limitations

Several limitations should be acknowledged. First, the single-arm, open-label design without a placebo control limits the ability to distinguish treatment effects from natural disease resolution and concomitant medications. Second, the sample sizes for certain special populations—particularly infants younger than 6 months and children with severe ALRTI—were small; therefore, optimal dosing and the specific efficacy and safety profile of AHSI in these groups require further investigation. Third, the absence of head-to-head comparisons with other commonly used expectorants (e.g., N-acetylcysteine) precludes definitive conclusions regarding the relative clinical advantages of AHSI in pediatric expectorant therapy. Fourth, the short follow-up period did not allow evaluation of long-term safety or ALRTI recurrence rates following AHSI treatment, indicating a need for extended follow-up studies. Fifth, the study was conducted exclusively in an inpatient setting, which excludes the large outpatient pediatric ALRTI population. Although the multicenter design provides geographic breadth, the findings cannot be directly extrapolated to ambulatory care, where the majority of cases are managed. Sixth, the exclusion criteria—including hepatic/renal dysfunction, malnutrition, and congenital respiratory diseases—created a relatively selected, “cleaned” population. These exclusions were retained as a safety precaution in this pragmatic, uncontrolled protocol involving a vulnerable pediatric population; however, they necessarily temper the naturalistic character of the study and limit the generalizability of the results to these excluded subgroups. Future investigations should therefore incorporate ambulatory settings and adopt broader eligibility criteria to enhance external validity.

Conclusions

This large-sample, multicenter real-world study demonstrates that a 7-day regimen of AHSI significantly alleviates cough and tenacious sputum symptoms in Chinese pediatric patients diagnosed with ALRTI, including both pneumonia and bronchitis. Treatment was associated with a low incidence of DRAEs, and no serious DRAEs were reported. Furthermore, AHSI showed excellent compatibility with a range of commonly used clinical nebulizers, regardless of brand or driving principle, when administered under standardized conditions. Based on these findings, AHSI can be recommended as an expectorant therapy for pediatric ALRTI, especially in cases marked by viscous sputum and difficulty in expectoration. It offers clinicians a treatment option with established efficacy, a favorable safety profile, and practical flexibility in clinical use.

Future research should focus on: (I) optimal dosing and safety in infants <6 months; (II) efficacy in severe ALRTI; (III) head-to-head comparisons with other expectorants; and (IV) long-term safety in children with chronic respiratory diseases.

Acknowledgments

We appreciate all the researchers, children, and parents who participated in the study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0178/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0178/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0178/prf

Funding: This study was sponsored by Beijing Hanmi Pharm. Co., Ltd. The funder had no role in the design and execution of the study, the development of the manuscript, or the decision to publish.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0178/coif). All authors report that this study was sponsored by Beijing Hanmi Pharm. Co., Ltd. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Institutional Review Boards of all participating institutions [Leading Medical Center: Beijing Children’s Hospital, Capital Medical University (No. [2020]-Y-016-C-01)], and adhered to the principles of the Declaration of Helsinki and its subsequent amendments, and Chinese Good Clinical Practice (GCP) guideline. Written informed consent was obtained from the legal guardians of all patients prior to the initiation of any study procedures.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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