Introduction

Chronic cough affects 5–10% of the general adult population, and it significantly impairs quality of life [1,2,3,4]. Chronic cough often presents with features of cough reflex hypersensitivity, making the identification and management of cough-triggering conditions or treatable traits essential for effective treatment [5,6,7]. Acid reflux is one of such treatable traits, and some patients with chronic cough report associated peptic symptoms, such as heartburn or acid regurgitation [8,9,10,11,12,13], for which acid suppressant treatment can be indicated [14, 15].

Proton pump inhibitors (PPIs) have long been the first-line treatment for acid-related conditions, such as gastroesophageal reflux disease (GERD) and peptic ulcers. PPIs have also shown benefits over placebos in improving cough in patients with chronic cough and confirmed acid reflux, although effects are limited or minimal in those without acid reflux [16, 17]. While PPIs are generally well-tolerated, certain limitations, such as the need for precise dosing timing and a relatively delayed onset of action, can impact patient adherence [18]. More than one third of patients with GERD taking PPIs may be unsatisfied with their treatment, with more than 60% using medications in addition to their prescribed medication [19].

Potassium-competitive acid blockers (P-CABs) are a newer class of acid-suppressants. P-CABs may offer therapeutic effects similar to PPIs and can be considered for both initial and maintenance treatment of GERD [20,21,22,23]. P-CABs may offer advantages in managing GERD-related symptoms due to their dosing convenience and potentially more rapid onset of action than PPIs [22]. Unlike PPIs, which irreversibly inhibit the proton pump under acidic conditions, P-CABs directly block potassium ions at the proton pump site, enabling more effective acid control throughout the day and night. P-CABs also bypass CYP 2C19 metabolism, lowering the risk of drug interactions [24].

However, the therapeutic role of P-CABs in alleviating cough in patients with GERD and chronic cough remains unexplored. Fexuprazan is a novel P-CAB, with potential advantages over PPIs, such as a more rapid onset of action and stable acid suppression [25]. In this background, we conducted a double-blind, active-controlled clinical trial to evaluate the efficacy and safety of fexuprazan compared to esomeprazole in treating GERD-related chronic cough.

Methods

Study Participants

This was a randomized, double-blind, active-controlled, multicenter, phase 4 exploratory trial conducted at eight sites in South Korea to evaluate the efficacy and safety of fexuprazan and to explore potential differences compared to esomeprazole in patients with GERD-related chronic cough (Clinical trial registration number: KCT0007746). Adult patients (aged 19–75 years) were eligible to participate if they had: (1) chronic cough for more than eight weeks at the time of screening, (2) active cough (defined by daily cough severity numerical rating scale [NRS] score ≥ 3 and Leicester Cough Questionnaire [LCQ] < 15) at the time of screening, and (3) a confirmed diagnosis of GERD with objective measurements at the time of screening or a history of recent peptic symptoms (heartburn or acid regurgitation) within the past month. Patients were excluded if they had been treated with a PPI, H2 blocker, or P-CAB within two weeks before randomization or if they had findings suggestive of other active causes of chronic cough or significant medical conditions. Detailed exclusion criteria are summarized in Supplementary Table 1.

Study Protocol

Patients presenting with chronic cough and meeting the eligibility criteria were recruited. Participants were also recruited through advertisements in hospitals or public transportation. At screening, detailed information on physician-diagnosed comorbidities was collected through interviews with the participants or by reviewing medical records. Participants were randomly assigned in a 1:1 ratio to receive either fexuprazan 40 mg (Daewoong Pharmaceutical Co., Ltd., Seoul, Korea) or esomeprazole 40 mg (AstraZeneca, Seoul, Korea) once daily, with matching placebos, for eight weeks (Fig. 1). The inclusion of a matched placebo (with identical appearance, taste, and smell) in both groups was intended to maintain blinding of participants and investigators to treatment allocation. A central randomization system ensured allocation concealment, and both investigators and participants were blinded. Study participants received two tablets (one active and one placebo) daily, with instructions to take the medication on an empty stomach, either before breakfast or before bedtime.

Fig. 1
figure 1

Study protocol overview. LCQ, Leicester Cough Questionnaire; RDQ, Reflux Disease Questionnaire; NRS, Numerical Rating Scale

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Participants attended the clinic at baseline (Day 0), and at weeks 1, 2, 4, and 8 for efficacy and safety assessments. During each visit, vital signs were monitored; adverse events were documented; and laboratory tests, including blood chemistry, hematology, and electrocardiograms, were performed. They were provided with a cough severity diary to document daily NRS scores for the first two weeks, which they returned at follow-up visits. Compliance was assessed by counting returned tablets at each visit, while adverse events were documented and graded using the Common Terminology Criteria for Adverse Events.

Since no prior studies have directly compared the two drugs for chronic cough, this exploratory study established a working hypothesis for research design purposes that the efficacy of fexuprazan would be similar to that of esomeprazole. Based on the LCQ’s minimal clinically important difference (MCID) of 1.3 points [26] and a standard deviation (SD) of 3.3, with a significance level of 2.5% and a power of 80%, a total sample size of 124 patients (62 per group) was calculated using PASS 2020 software. With a 20% dropout rate, 156 patients (78 per group) were targeted. The Safety Set included all randomized patients who received at least one dose of the study medication. The Full Analysis Set (FAS) comprised patients from the Safety Set who also had at least one efficacy evaluation. The Per-Protocol Set (PPS) consisted of patients from the FAS who completed the study without major protocol violations, such as failure to meet inclusion/exclusion criteria, use of prohibited concomitant medications, or adherence below 80%.

Endpoints

The primary endpoint was changes in the total LCQ score at Week 8 (compared to baseline), with a clinically significant response defined as LCQ improvement ≥ 1.3 points (MCID). The secondary endpoints included changes in daily cough severity, measured by the NRS scores (0–10, with higher scores indicating more severe cough) at Weeks 1, 2, 4, and 8, and changes in the Reflux Disease Questionnaire (RDQ) scores at the same time points. The cough severity NRS score was collected daily for the first two weeks.

The RDQ is a self-administered questionnaire comprising 12 items to assess the frequency and severity of heartburn, acid regurgitation, and dyspepsia. Each item for frequency and severity was scored on a 6-point Likert scale, ranging from 0 to 5, with higher scores indicating more severe or frequent symptoms [27]. The RDQ mean score was calculated as the mean of the responses to the 12 items, resulting in a possible score range of 1 to 6. The RDQ has been a validated tool for assessing anti-reflux treatment clinical trials [27]. For sensitivity analysis, respondents were categorized according to baseline RDQ scores as having mild (< 2.8), moderate (2.8–3.9), or severe (≥ 3.9) symptoms [28]. Safety outcomes included the incidence of adverse events, vital signs, physical examinations, and laboratory findings.

Ethical Considerations.

This study adhered to the Declaration of Helsinki and was approved by the institutional review boards IRBs of all participating institutions (IRB number: 2022-06-089). All participants provided written informed consent before enrolment.

Statistical Analysis

All efficacy endpoints were analyzed using the FAS, including all randomized patients who received at least one dose, following the intention-to-treat principle. The PPS included protocol-adherent participants. Safety endpoints were analyzed in the safety population, including patients who received fexuprazan or placebo at all protocol-specified times, regardless of group assignment.

Continuous variables were presented as mean ± SD or as median and interquartile range (IQR), depending on their distribution. Categorical variables were summarized as numbers and percentages. Baseline differences between groups were assessed using the t-test, Mann–Whitney U test, Pearson’s χ2 test, or Fisher’s exact test, as appropriate. Changes in questionnaire scores from baseline were compared between groups using the independent samples t-test. A mixed model for repeated measures was employed to analyze longitudinal data, with fixed effects for treatment, visit, and their interaction. The model was adjusted for site, baseline NRS, site-by-visit interaction, and baseline NRS-by-visit interaction. Least squares (LS) means were calculated to account for baseline differences between groups. All statistical analyses were performed using STATA, and a p-value < 0.05 was considered statistically significant.

Results

Baseline Characteristics of the Study Participants

A total of 190 patients with GERD-related chronic cough were recruited as potential candidates, and 161 patients met the selection criteria and were randomized to fexuprazan (N = 80) or esomeprazole (N = 81). Among them, 150 completed the study (Supplementary Fig. 1).

The baseline characteristics of the participants are detailed in Table 1. The mean age was 39 ± 12 years in the fexuprazan group and 40 ± 12 years in the esomeprazole group (p = 0.956). A higher proportion of females was observed in the fexuprazan group than in the esomeprazole group (76% vs. 52%; p = 0.001). Other baseline parameters were comparable between the two groups. The baseline LCQ score was 11.7 ± 2.8 in the fexuprazan group and 10.8 ± 2.7 in the esomeprazole group (p = 0.068). Baseline cough NRS scores were 6.0 ± 1.9 and 5.6 ± 1.7, respectively (p = 0.171), while baseline RDQ scores were 2.5 ± 1.2 and 2.3 ± 1.0, respectively (p = 0.221).

Table 1 Baseline characteristics of study participants
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Change in LCQ Scores After 8 weeks of Treatment

At Week 8 after treatment initiation, the fexuprazan group demonstrated significant improvements in LCQ scores from baseline, comparable to those observed in the esomeprazole group (Table 2, Fig. 2A, B). The mean change in LCQ total score at Week 8 was + 4.9 ± 4.0 in the fexuprazan group and + 5.3 ± 3.8 in the esomeprazole group (p = 0.558). Improvements were consistently noted across all LCQ domains—physical, psychological, and social—without significant differences between the two treatment groups (Fig. 3). Clinically significant responses (defined as an LCQ score improvement of ≥ 1.3) were observed in 78% of patients in the fexuprazan group and 79% in the esomeprazole group (p = 0.798).

Table 2 Change in LCQ, cough NRS, and RDQ scores from baseline after 8 weeks of treatment
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Fig. 2
figure 2

A Leicester Cough Questionnaire (LCQ) scores over 8 weeks of treatment, and changes in B LCQ score, C cough severity numerical rating scale (NRS), and D reflux disease questionnaire (RDQ) score from baseline to 8 weeks. All values are presented as means (bars) with 95% confidence intervals (whiskers)

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Fig. 3
figure 3

Improvements in the physical, psychological, and social domains of the Leicester Cough Questionnaire (LCQ), presented as means (dots) and 95% confidence intervals (whiskers)

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Change in Secondary Efficacy Outcomes

Cough severity NRS scores were reduced in both treatment groups at week 8, with a mean change of − 3.8 ± 2.7 in the fexuprazan group and − 3.1 ± 2.1 in the esomeprazole group. However, there was no statistically significant difference between the two groups (p = 0.073) (Table 2, Fig. 2C, D). Over the 8-week treatment period, both treatment groups also demonstrated a similar pattern of reduction in daily cough severity NRS scores (Supplementary Table 2). Improvements in RDQ total scores were similar between the two groups, with mean changes of − 1.8 ± 1.3 in the fexuprazan group and − 1.5 ± 1.2 in the esomeprazole group (p = 0.230) (Table 2).

Exploration of LCQ and Cough Severity NRS Score Changes According to Baseline RDQ Responses

To explore whether baseline reflux symptom severity influenced treatment response, a post hoc sensitivity analysis was performed by stratifying study participants into mild, moderate, and severe categories, based on baseline RDQ scores (Supplementary Table 3). In the mild subgroup, the mean improvement in LCQ score was significantly greater in the esomeprazole group compared to the fexuprazan group (n = 87; 5.5 ± 0.5 vs. 4.0 ± 0.5, p = 0.034), whereas the change in cough NRS scores was comparable between groups (n = 91; − 3.0 ± 2.7 vs. − 2.9 ± 2.1, p = 0.890). In the moderate subgroup, no significant differences were observed between the two groups for either LCQ or NRS scores. Among those with severe reflux symptoms, LCQ score improvements were numerically greater in the fexuprazan group than in the esomeprazole group, but the difference did not reach statistical significance (n = 15; 8.3 ± 2.8 vs. 6.7 ± 1.7, p = 0.370). However, a significant improvement in cough NRS scores was observed in favour of fexuprazan (n = 14; − 6.5 ± 2.8 vs. − 3.4 ± 2.4, p = 0.040).

Safety and Adverse Events

The incidence of treatment-emergent adverse events (TEAEs) was comparable between the two groups (Table 3). The most frequently reported adverse events were nasopharyngitis, headache, nausea, dizziness and dyspepsia. Serious adverse events were rare, with only one serious TEAE reported in the esomeprazole group, which was ligament sprain. Adverse drug reactions were reported in 19% of patients in the fexuprazan group and 16% in the esomeprazole group (p = 0.651). One patient in the fexuprazan group discontinued treatment owing to upper gastric pain and nausea. No deaths occurred in either group.

Table 3 Summary of treatment-emergent adverse events (TEAEs) (n = 161)
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Discussion

This 8-week, double-blind, active-controlled, multicenter exploratory study demonstrates that fexuprazan, a novel P-CAB, is comparable to esomeprazole, a PPI, in improving cough-related quality of life and reducing cough severity in patients with GERD-related chronic cough. These findings support the potential of P-CABs as a promising alternative to PPIs for managing acid reflux-related chronic cough.

A key consideration in interpreting these findings is the absence of a placebo-only treatment group, which raises a question about the true therapeutic benefit of acid suppressants, including PPIs and P-CABs. Placebo effects and regression to the mean can be substantial in chronic cough studies [29, 30]. Importantly, as demonstrated in a systematic review by Kahrilas and colleagues, the actual therapeutic benefit of acid suppressants may be minimal in patients without pathologic acid reflux [16]. However, the effect size observed in this study (mean LCQ score change of + 4.9 in the fexuprazan treatment group) was relatively larger than those reported in placebo treatment groups from the COUGH-1 & 2 trials of refractory or unexplained chronic cough (approximately + 2.5 at 8 weeks) [31], and from a previous trial comparing esomeprazole and placebo in patients with GERD-related chronic cough by Faruqi and colleagues (+ 0.7) [17]. Although direct comparisons are limited by differences in trial design and populations, we speculate that the magnitude of improvement observed in this study may exceed typical placebo responses, suggesting that the cough improvement associated with fexuprazan treatment may not be solely attributable to placebo effects.

In the existing literature, research on the effectiveness of P-CABs for GERD-related chronic cough remains limited. The few studies published to date have typically used PPIs as comparators, presumably because PPIs have been widely studied for this condition [22, 32,33,34]. Zhong et al. recently reported the comparable, or potentially superior, efficacy of vonoprazan over esomeprazole in 66 patients with chronic cough and GERD in China [32]. Both medications demonstrated similar efficacy in cough relief, with the vonoprazan group showing greater improvement in cough-related quality of life after two months of treatment. However, the study employed an open-label design, which could not control the risk of bias owing to the lack of binding, potentially influencing both the researchers’ assessments and the participants’ reports. In this regard, the present study adds more robust evidence to support the use of P-CABs for the management of GERD-related chronic cough, through a double-blind randomized controlled trial with a larger sample size.

The mechanisms of action of P-CABs are similar to those of PPIs in that both target the gastric proton pump. However, unlike PPIs, P-CABs block the H+, K+ ATPase pump without requiring acid activation, allowing for a rapid onset of action [35]. In contrast, PPIs have a gradual onset of effect, a short plasma half-life (approximately 1–2 h), and typically require 3–5 days of once-daily intake to reach pharmacodynamic steady-state [36]. The potential benefits of the rapid onset of action associated with P-CABs have been reported in a randomized controlled trial involving patients with laryngopharyngeal reflux [33]; the trial demonstrated that fexuprazan treatment resulted in a greater improvement in the individual Reflux Symptom Index item score for “troublesome cough” after four weeks. Moreover, in a study of patients with erosive esophagitis, the proportion of subjects reporting chronic cough (based on a binary response) was reduced after fexuprazan treatment compared to esomeprazole treatment [22]. However, those studies did not utilize validated endpoints for cough measurement. Our trial utilized the LCQ, one of the most widely used and validated patient-reported outcomes [4]; however, it did not demonstrate significant superiority of fexuprazan over esomeprazole.

We then conducted a sensitivity analysis to explore potential differences in therapeutic benefits between fexuprazan and esomeprazole based on baseline RDQ severity. Esomeprazole appeared more effective in the mild reflux group, whereas fexuprazan showed greater benefit in the severe group, suggesting the possibility of differential therapeutic effects depending on the severity of acid reflux. However, no definitive conclusions could be drawn due to the exploratory nature of the sensitivity analysis and the small sample size in the severe reflux subgroup. These findings underscore the need for further investigation into the comparability of fexuprazan and PPIs in the management of acid reflux–related chronic cough.

The efficacy of PPIs is dependent on adherence to dosing instructions, requiring administration 30–60 min before meals to optimize acid suppression [18, 36]. However, real-world data indicate that considerable portion of patients with GERD report dissatisfaction with PPI therapy, often due to suboptimal symptom control and strict dosing requirements [19]. P-CABs may offer a practical advantage as they do not require pre-meal administration, allowing for more flexible dosing and potentially improving treatment adherence. Additionally, P-CABs provide more stable [36] and sustained acid suppression, independent of food intake, which may be beneficial in the real-world management of acid reflux–related chronic cough.

Older age is typically considered a risk factor for GERD [37]. However, our study population was relatively young, with a mean age of 39 years, which may warrant further discussion. We speculate that this demographic profile may be attributed to the strict eligibility criteria used in our clinical trial, as well as to the evolving epidemiology of GERD in Asian countries. Watanabe et al. [38] reported that GERD prevalence was highest in the 20–29 age group of Japanese population, with a decline observed in the elderly. Lifestyle and dietary habits, such as high-stress levels, irregular eating patterns, and increased consumption of reflux-inducing foods, have been associated with the increase of GERD in young Asian populations.

The safety profiles of both medications in this study were comparable. The TEAEs included gastrointestinal side effects and nasopharyngitis, which are commonly associated with acid-suppressing therapies. No serious adverse events (SAEs) were reported in the fexuprazan group, further supporting its safety for patients with GERD-related chronic cough.

Several limitations warrant consideration. First, although participants were randomized, an unintentional gender imbalance occurred between the two groups. Second, we measured only subjective outcomes for changes in cough, whereas objective cough frequency could provide additional insights and should be included as a main outcome to confirm the effects on cough. Third, the study duration also may have been insufficient to assess long-term efficacy and tolerability. Finally, objective measures of acid reflux, such as esophageal pH monitoring, were not included to confirm pathological acid reflux. Incorporating pH-impedance monitoring and DeMeester scores could help identify patients more likely to benefit from acid suppression therapy by quantifying esophageal acid exposure and reflux burden. While we agree that objective measures increase the internal validity of the treatment effects, they can hinder and complicate participant recruitment [39]. The symptom-based selection criteria used in our study correspond to the indications for acid suppressant therapy suggested by current guidelines for chronic cough [5, 14, 15, 40]. These criteria were intentionally designed to reflect the clinical context and real-world applicability of guideline recommendations. Therefore, our findings should be interpreted within that framework.

Despite these limitations, this study adds valuable insights to the growing body of literature on P-CABs, supporting their potential utility as alternatives to PPIs for managing GERD-related chronic cough.

In conclusion, fexuprazan was shown to be as effective and tolerable as esomeprazole in improving cough-related quality of life and reducing cough severity in GERD-related chronic cough. Rapid onset of action, sustained acid suppression, and convenient once-daily dosing may position fexuprazan as a promising option for patients with chronic cough requiring acid suppression therapy. Further studies with longer durations, larger sample sizes, and more diverse patient populations are warranted to confirm these findings and establish fexuprazan as part of the treatment pathways for chronic cough associated with acid reflux.