Evaluation of the Safety and Efficacy of K-CAB (Tegoprazan) as Symptomatic Maintenance Therapy in Patients With NERD: A Multicenter, Randomized Double-Blinded Controlled Trial
Article information
, Joong Goo Kwon,2, June Hwa Bae2, Hyeong Ho Jo2, Eun Young Kim2, Seong Woo Jeon1, Yun Jin Chung1, Ju Yup Lee3, Kyung Sik Park3, Si Hyung Lee4, Chang Hun Yang4, Daegu-Gyeongbuk Gastrointestinal Study GroupAbstract
Objectives
This preliminary, randomized, double-blind, multi-center study evaluated the efficacy of alternate-day tegoprazan (50 mg) versus daily lansoprazole (15 mg) as for maintenance therapy in patients with non-erosive reflux disease (NERD).
Methods
Forty five participants were enrolled and treated for 8 weeks. The primary endpoint was the proportion of symptom-free days. The secondary endpoints were changes in Gastrointestinal Symptom Rating Scale (GSRS) and Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) scores.
Results
It showed no significant difference between groups in the proportion of symptom-free days between both groups (tegoprazan: 60.4%±6.3%; lansoprazole: 74.0%±6.5%). The GSRS and GERD-HRQL score improvements were also comparable between both groups. Both treatments were well tolerated, with no serious adverse events reported.
Conclusions
These findings suggest that alternate-day tegoprazan offers comparable efficacy and safety to daily lansoprazole therapy and may serve as a more flexible and patient-friendly maintenance option for NERD.
INTRODUCTION
Gastroesophageal reflux disease (GERD) is characterized by the backflow of gastric contents into the esophagus due to dysfunction of the lower esophageal sphincter [1]. While some patients with GERD develop erosive esophagitis, a substantial proportion exhibit typical reflux symptoms, such as heartburn and acid regurgitation, without visible mucosal breaks on endoscopy. This is known as non-erosive reflux disease (NERD). NERD can significantly impair the patient’s quality of life despite the absence of mucosal injury [2]. Proton pump inhibitors (PPIs), which suppress gastric acid production by irreversibly inhibiting H+/K+ ATPase in parietal cells, is often used as maintenance therapy for NERD [3]. Although effective, PPIs require daily use, which is associated with challenges, such as suboptimal adherence, meal-timing constraints, inter-patient variability due to CYP2C19 metabolism, and potential long-term safety concerns [3]. Potassium-competitive acid blockers (P-CABs) have emerged as a new class of acid suppressants with several advantages over PPIs [4]. Unlike PPIs, P-CABs, such as tegoprazan, act rapidly and reversibly on gastric H+/K+ ATPase by competing with potassium ions, providing a faster onset of action and more sustained acid suppression, leading to a more stable control of intragastric pH [4,5]. These pharmacological characteristics support the potential for less frequent dosing schedules. Preliminary data suggest that alternate-day administration of P-CABs may achieve symptom control comparable to daily PPI regimens while reducing medication burden and improving adherence [6-8].
This study aimed to conduct a preliminary exploration of the efficacy of alternate-day 50 mg tegoprazan compared with daily 15 mg lansoprazole in maintaining symptom relief in NERD patients previously responsive to treatment.
METHODS
Study design and participants
This was a multi-center, double-blind, randomized, activecontrolled, clinical trial. Patients aged 19–65 years with a clinical diagnosis of NERD, defined by the presence of typical reflux symptoms (heartburn, regurgitation, or both occurring more than twice a week) and the absence of mucosal breaks on upper endoscopy, for which they had received PPI therapy for a minimum of 4 weeks and who demonstrated symptom improvement after a washout period of at least 2 weeks were screened for eligibility. Heartburn was defined as a burning sensation behind the breastbone. Regurgitation was defined as the sensation of effortless return of stomach contents into the upper throat. The key exclusion criteria included a history of gastrointestinal surgery, recent use of acid-suppressive therapy, and serious comorbid conditions. All the participants provided written informed consent. Eligible patients were randomly assigned in a 1:1 ratio to receive either alternate-day tegoprazan (50 mg) or daily lansoprazole (15 mg) for eight weeks. Blinding was maintained using a matching placebo (Fig. 1). The study protocol was approved by the institutional review board of each participating institution, including the Daegu Catholic University Medical Center (CR-19-086-L, KNUCH 2019-05-013, DSMC 2019-06-020, and YUMC 2019-08-035), and the study was registered at cris.nih.go.kr (KCT0004401).
Flow diagram showing the study protocol. GSRS, Gastrointestinal Symptom Rating Scale; GERD-HRQL, Gastroesophageal Reflux Disease-Health Related Quality of Life.
Efficacy assessments
The primary efficacy endpoint was the proportion of symptom-free days during the 8-week maintenance treatment period, which was defined as days without heartburn or acid regurgitation. Patients recorded their daily symptoms in standardized diaries, and data were analyzed in both the full analysis set (FAS) and the per-protocol set (PPS). Secondary endpoints included changes in the Gastrointestinal Symptom Rating Scale (GSRS) and GERD-Health-Related Quality of Life (GERD-HRQL) scores. GSRS was administered at baseline and at weeks 2, 4, and 8. The GSRS score is the sum of 32 items, ranging from 0 to 100 and standardized from 32 to 160. The GERD-HRQL questionnaire was completed at baseline and week 8. The GERD-HRQL score is the sum of the 10 items, with values ranging from 0 to 50.
Safety assessment
All adverse events (AEs) were recorded, with special attention paid to treatment-related adverse drug reactions (ADRs). Safety assessments included physical examinations, laboratory tests, and monitoring of vital signs.
Statistical analysis
Descriptive statistics were used to summarize the demographic and baseline characteristics. Continuous variables of the proportion of symptom-free days during the 8-week maintenance treatment period were expressed as LS-Means±standard error, while other continuous variables were expressed as means±standard deviations. Categorical variables are presented as frequencies and percentages. Between-group comparisons were conducted using Student’s t-test or the Mann–Whitney U test for continuous variables, and the chi-square test or Fisher’s exact test for categorical variables. The primary endpoint was analyzed using analysis of covariance after adjusting for symptoms. Statistical significance was set at p<0.05. significant. All analyses were conducted using the FAS and PPS populations.
RESULTS
Subject disposition and baseline characteristics
A total of 50 subjects were screened, of whom 45 were enrolled and randomized. Of these, 23 participants were assigned to receive tegoprazan every other day, and 22 received lansoprazole daily. Three patients in the tegoprazan group discontinued from the study early, two withdrew their consent, and one discontinued the study based on the investigator’s decision. In contrast, all the patients in the lansoprazole group completed the trial (Fig. 2). The baseline demographic and clinical characteristics were similar between the two treatment groups, with no statistically significant differences in age, sex distribution, or baseline symptom scores. The treatment adherence rates for the tegoprazan and lansoprazole groups were 93.7% and 91.1% (p=0.819) in the FAS population and 97.3% and 95.3% (p=0.737) in the PPS population, respectively.
Randomization protocol and patient disposition.
Primary endpoint
In the FAS population, the LSMean proportion of symptom-free days during the 8-week period was 60.4%±6.3% in the tegoprazan group (n=21) and 74.0%±6.5% in the lansoprazole group (n=20), but this difference was not statistically significant (p=0.143). In the PPS analysis, the LSMean proportion of symptom-free days was 67.8%±6.7% in the tegoprazan group (n=16) and 75.1%±6.7% in the lansoprazole group (n=16), again with no significant difference (p=0.458). These results suggest that alternate-day administration of tegoprazan 50 mg provides comparable efficacy to the daily administration of 15 mg lansoprazole in maintaining symptom relief in patients with NERD.
Secondary endpoints
GSRS scores
In the FAS population, the mean GSRS score at 2, 4, and 8 weeks was 9.2±8.9, 6.8±7.6, and 5.0±4.8 in the tegoprazan group and 10.7±10.0, 8.9±8.8, and 5.6±5.2 in the lansoprazole group, respectively (Fig. 3A). The mean GSRS score changes at weeks 2, 4, and 8 showed statistically significant differences compared with the baseline scores in both groups (p<0.005). However, there were no statistically significant differences between the two groups at 2, 4, and 8 weeks (Fig. 3B). In the PPS population, the mean GSRS score at 2, 4, and 8 weeks was 10.3± 9.5, 6.6±8.0, and 4.8±4.6 in the tegoprazan group and 10.6± 10.6, 9.1±9.8, and 5.4±5.7 in the lansoprazole group, respectively (Fig. 3C). The mean GSRS score changes at weeks 2, 4, and 8 showed statistically significant differences compared with the baseline scores in both groups (p<0.005) in PPS analysis. In addition, there were no statistically significant differences between the two groups at 2, 4, and 8 weeks (Fig. 3D).
Mean changes in GSRS at 2, 4, and 8 weeks compared to the baseline. FAS (A and B) and PPS (C and D) score. *p<0.005. GSRS, Gastrointestinal Symptom Rating Scale; FAS, full analysis set; PPS, per-protocol set; ns, not significant.
GERD-HRQL scores
Fig. 4 shows the mean GERD-HRQL scores at baseline and at week 8 in both treatment groups. In the FAS, the mean change in GERD-HRQL score from baseline to week 8 was -7.1± 4.5 in the tegoprazan group (p<0.001) and -8.1±8.3 in the lansoprazole group (p<0.001). However, there was no statistically significant difference between the two groups in the change in the GERD-HRQL score (p>0.999) (Fig. 4A). In the PPS, the similar changes were -7.4±5.0 in tegoprazan group (p<0.001) and -8.4±8.8 in lansoprazole group (p=0.002), respectively. Both treatment groups showed significant within-group improvements, with no significant differences between the two groups (p>0.999) (Fig. 4B).
Mean changes in the quality of life (GERD-HRQL) at 8 weeks compared to the baseline. FAS (A) and PPS (B) score. GERD-HRQL, Gastroesophageal Reflux Disease-Health-Related Quality of Life; FAS, full analysis set; PPS, per-protocol set.
Safety
The incidence and severity of AEs were similar between groups. The most common ADRs were mild gastrointestinal symptoms such as constipation, abdominal distension, cramps in the lower abdomen, and loose stool. No serious AEs or treatment-related discontinuation were noted. The safety profile of alternate-day tegoprazan administration was consistent with previously reported data.
DISCUSSION
This preliminary trial did not detect a statistically significant difference between alternate-day tegoprazan and daily lansoprazole in addressing NERD symptoms. Both treatment groups showed significant improvements from baseline in the proportion of symptom-free days and GSRS scores at weeks 2, 4, and 8, with no significant differences between the groups. The GERD-HRQL scores also improved significantly within each group without significant intergroup differences. These findings suggest that alternate-day tegoprazan is an effective alternative to lansoprazole for maintenance therapy in patients with NERD. Our results support the use of a flexible dosing strategy that may improve patient adherence, reduce drug exposure, and offer a practical alternative to daily PPI therapy. Previous studies have shown that P-CABs can lead to high rates of mucosal healing in erosive esophagitis and reduce relapse during maintenance therapy [6,9]. Although direct comparisons in NERD populations are limited, evidence from retrospective and cohort studies suggests that P-CABs are effective even in PPI-refractory cases [10]. The pharmacological advantages of P-CABs, including rapid onset, long-lasting acid suppression, and independence from CYP2C19 metabolism. These advantages support the use of P-CABs in alternate-day or on-demand regimens. P-CABs may address common limitations of PPIs, such as adherence issues and long-term safety concerns [11]. Importantly, alternate-day P-CAB therapy may help maintain quality of life while minimizing the medication burden.
This study has several limitations. First, the 8-week treatment duration may not be sufficient to evaluate long-term outcomes, such as recurrence and sustained symptom remission. Second, patients with functional heartburn or reflux hypersensitivity may have been enrolled because confirmatory pH monitoring or impedance testing was not performed. Third, the small sample size (n=45) limited the statistical power and generalizability of the results. The target sample size was 60 participants in each group. Nevertheless, accrual to maintenance-phase NERD trials is intrinsically difficult. Without endoscopic evidence of the disease, many otherwise eligible patients are reluctant to undergo prolonged follow-up, which limits their enrollment.
Despite these limitations, this study provides valuable preliminary evidence supporting the feasibility and clinical utility of alternate-day tegoprazan administration in NERD. Future studies with larger sample sizes, longer follow-up periods, and more diverse populations to confirm and extend these findings are warranted.
This randomized controlled trial demonstrated that alternate-day tegoprazan 50 mg was comparable to daily lansoprazole 15 mg in symptom control among patients with NERD. Both regimens resulted in significant improvements in symptom frequency, severity, and quality of life, with favorable safety profiles. Alternate-day P-CAB therapy may be an effective, convenient, and patient-friendly option for long-term management of NERD. To validate these results and support their clinical implementation in the future, large-scale studies are warranted.
Notes
Availability of Data and Material
Research data are not shared.
Conflicts of Interest
Yong Hwan Kwon and Ju Yup Lee, contributing editors of the Korean Journal of Helicobacter and Upper Gastrointestinal Research, were not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.
Funding Statement
This study was funded in full by HK inno.N Corp, Gyeonggi-do, Korea (Study No. KCAB_001).
Acknowledgements
None
Authors’ Contribution
Conceptualization: Yong Hwan Kwon, Joong Goo Kwon. Data curation: Yong Hwan Kwon. Formal analysis: Yong Hwan Kwon. Funding acquisition: Joong Goo Kwon. Investigation: Yong Hwan Kwon, Joong Goo Kwon, June Hwa Bae, Hyeong Ho Jo, Seong Woo Jeon, Yun Jin Chung, Ju Yup Lee, Kyong Sik Park, Si Hyung Lee, Chang Hun Yang. Methodology: Yong Hwan Kwon. Supervision: Joong Goo Kwon, Eun Young Kim. Visualization: Yong Hwan Kwon. Writing—original draft: Yong Hwan Kwon. Writing—review & editing: Yong Hwan Kwon, Joong Goo Kwon, Hyeong Ho Jo, Seong Woo Jeon, Kyung Sik Park, Si Hyung Lee, Chang Hun Yang. Approval of final manuscript: all authors.