Efficacy of 7-day and 14-day potassium-competitive acid blocker-based bismuth-containing quadruple regimen for Helicobacter pylori infection

Abstract

BACKGROUND

Potassium-competitive acid blocker-based regimens may offer advantages over proton pump inhibitor-based regimens for Helicobacter pylori (H. pylori) eradication by suppressing gastric acid secretion more strongly and rapidly.

AIM

To compare the effectiveness and tolerability of 7-day and 14-day potassium-competitive acid blocker-based bismuth-containing quadruple regimen (PC-BMT) against a 14-day proton pump inhibitor-based bismuth-containing quadruple regimen (P-BMT) in settings with ≥ 15% clarithromycin resistance.

METHODS

Treatment-naïve H. pylori patients were assigned in a random one of three groups: (1) 7-day PC-BMT (tegoprazan 50 mg twice daily, bismuth 120 mg four times daily, metronidazole 500 mg three times daily, and tetracycline 500 mg four times daily); (2) 14-day PC-BMT; and (3) 14-day P-BMT. Compliance, eradication rates, and treatment-related adverse events were evaluated across the three groups.

RESULTS

The intention-to-treat (ITT) analysis included 119 patients, 118 patients, and 117 patients in the 7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT groups, respectively. In the modified ITT population, eradication rates were 80.5%, 83.8%, and 80.5%, and the per-protocol rates were 81.7%, 87.5%, and 79.3%, respectively. The 14-day PC-BMT was non-inferior to the 14-day P-BMT in modified ITT and per-protocol analyses but not in the ITT analysis. The 7-day PC-BMT regimen was not non-inferior to the 14-day P-BMT regimen. Treatment-related adverse events occurred in 19.3%, 29.7%, and 26.5% of patients, with no serious events and no significant between-group differences. Compliance exceeded 95% across all regimens.

CONCLUSION

The 14-day PC-BMT regimen demonstrated non-inferior efficacy, acceptable safety, and high compliance compared with the 14-day P-BMT regimen, suggesting it may serve as a viable treatment option for H. pylori eradication when clarithromycin resistance is ≥ 15%.

Key Words: Helicobacter pylori; Potassium-competitive acid blockers; Proton pump inhibitors; Bismuth-containing quadruple therapy; Bismuth-metronidazole; Tetracycline

Core Tip: Bismuth-containing quadruple therapy is recommended as first-line treatment for Helicobacter pylori in regions with high clarithromycin resistance, yet the optimal acid suppressant and treatment duration remain unclear. This multicenter randomized trial is the study to evaluate tegoprazan, a potassium-competitive acid blocker, within a bismuth-metronidazole-tetracycline quadruple regimen. The 14-day tegoprazan-based regimen achieved non-inferior eradication compared with the conventional 14-day proton pump inhibitor-based regimen, whereas the 7-day regimen did not. These results highlight that tegoprazan-based bismuth quadruple therapy requires a 14-day duration to ensure adequate eradication efficacy.

INTRODUCTION

Helicobacter pylori (H. pylori) infection is among the most common bacterial infections of the upper gastrointestinal tract[1]. Despite the development of multiple eradication regimens over the past few decades, the prevalence of H. pylori infection remains high, affecting an estimated 45% of the global population[1]. In Korea, H. pylori infection remains a significant public health burden[2].

A major contemporary challenge in H. pylori treatment is the increasing antibiotic resistance, particularly to clarithromycin, metronidazole, and levofloxacin[3]. This increasing resistance has significantly reduced the efficacy of conventional triple therapy, especially in areas where resistance to clarithromycin is ≥ 15%. In response, international guidelines, including the Maastricht VI/Florence consensus report, the American College of Gastroenterology guidelines, and the Toronto consensus, now recommend 14-day bismuth-based quadruple therapy (BQT) or non-bismuth quadruple concomitant therapy as the preferred first-line approach where antibiotic resistance is prevalent[4-6]. In Korea, BQT is still primarily considered a second-line treatment following clarithromycin-based triple therapy failure[7]. Nevertheless, as clarithromycin-resistant strains become more widespread, BQT is progressively being adopted as an initial eradication strategy. A key merit of BQT in this scenario is that its performance is preserved despite clarithromycin resistance, rendering it an attractive therapeutic choice[8,9].

Proton pump inhibitors (PPIs) have long been the standard acid-suppressive agents used in H. pylori eradication therapy. However, their pharmacodynamic limitations, including slow onset of action, inter-individual variability due to CYP2C19 polymorphisms, and insufficient acid suppression, can hinder successful H. pylori eradication[10]. Tegoprazan and other potassium-competitive acid blockers (P-CABs) represent a newer category of acid-suppressive drugs that can overcome several limitations of PPIs. P-CABs provide rapid, potent, and sustained gastric acid suppression, thereby enhancing antibiotic efficacy by maintaining an intragastric pH conducive to optimal antibiotic activity[11]. In Korea, tegoprazan has been covered by the National Health Insurance for antibiotic combination therapy for H. pylori eradication since July 1, 2023.

Given the rising prevalence of antibiotic resistance and the pharmacological advantages of P-CABs, their incorporation into bismuth-based quadruple regimens may improve eradication efficacy. In this study, we set out to evaluate the effectiveness and tolerability of two P-CAB-based bismuth-containing quadruple regimen (PC-BMT), administered for either 7 days or 14 days, against a standard 14-day PPI-based bismuth-containing quadruple regimen (P-BMT) in the first-line management of H. pylori infection.

MATERIALS AND METHODS

Study design

This research was designed as a prospective, multicenter, open-label, randomized trial to assess non-inferiority. The study was conducted between October 2022 and July 2024 across five medical centers within the Hallym University network: (1) Hallym University Sacred Heart Hospital; (2) Chuncheon Sacred Heart Hospital; (3) Dongtan Sacred Heart Hospital; (4) Kangnam Sacred Heart Hospital; and (5) Kangdong Sacred Heart Hospital. Patients who were treatment-naïve and diagnosed with H. pylori infection were allocated randomly into one of three therapeutic arms: (1) 7-day PC-BMT: A 7-day regimen comprising tegoprazan 50 mg twice daily, bismuth 120 mg four times daily, metronidazole 500 mg three times daily, and tetracycline 500 mg four times daily; (2) 14-day PC-BMT: The same P-CAB-based bismuth-containing regimen administered for 14 days; and (3) 14-day P-BMT: A 14-day PPI-based bismuth-containing regimen (control group) consisting of rabeprazole 20 mg twice daily combined with the same antibiotics and bismuth dosage as above.

The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The protocol approval was obtained from the Korean Ministry of Food and Drug Safety and the Institutional Review Board (approval no. 2021-09-013-001). Written informed consent was obtained from every participant before enrollment. This trial complied with the CONSORT standards and was registered in the International Clinical Trials Registry Platform under the identifier KCT0007444 in June 2022.

Study population

The study enrolled adults aged 19 years or above who had received an upper gastrointestinal endoscopy within 4 weeks prior to screening and had a confirmed H. pylori infection. Exclusion criteria comprised the following: (1) A history of prior gastric resection surgery; (2) Known allergies or adverse reactions to any of the investigational drugs; (3) Intake of PPIs or P-CABs within 2 weeks prior to randomization; (4) Use of antibiotics or bismuth-containing agents within the preceding 4 weeks; (5) Current pregnancy, breastfeeding, or refusal to practice contraception during the study; (6) Concurrent use of contraindicated medications, specifically: Ticagrelor, cyclosporine, astemizole, pimozide, dihydroergotamine, ergotamine, lovastatin, simvastatin, atorvastatin, mizolastine, indinavir, ritonavir, terfenadine, human immunodeficiency virus protease inhibitors (such as nelfinavir or atazanavir), or bepridil; and (7) Presence of severe comorbidities, including hematological disorders, central nervous system infections, or infectious mononucleosis.

Study protocol

The procedural timeline is outlined in Figure 1. During the screening phase, baseline demographic data and medical history, including any prior eradication therapy for H. pylori, were recorded. At visit 1, participants underwent a physical examination, assessment of vital signs, laboratory testing, and pregnancy testing. Confirmation of H. pylori infection was established via the rapid urease test, the 13C-urea breath test (UBT), or histological analysis. During endoscopic evaluation, two biopsies were collected from the gastric corpus and antrum for Giemsa staining for histology or rapid urease test (Pronto Dry New; Medical Instruments Corp., Herford, Germany). To assess antibiotic resistance, two additional biopsies from the corpus and antrum were obtained and cultured using the agar dilution technique. For antibiotic susceptibility testing, further biopsies from the corpus and antrum were processed via the agar dilution method, as detailed previously[12]. Resistance testing was not performed for patients whose diagnosis was based solely on UBT and who had already undergone endoscopy.

Figure 1 Study design. P-BMT: Proton pump inhibitor-based bismuth-containing quadruple regimen; PC-BMT: Potassium-competitive acid blocker-based bismuth-containing quadruple regimen.

Eligible patients were randomized at visit 2 into one of three treatment arms in a 1:1:1 ratio using a web-based system that employed a computer-generated stratified permuted block algorithm (block sizes of 2, 4, or 6). The allocation sequence remained concealed from investigators until the assignment. Participants were educated on potential side effects and were monitored for treatment-related adverse events (TRAEs) via a telephone call at day 7 or day 14 (± 14 days) following therapy completion (visit 3).

A follow-up UBT was conducted at least 4 weeks post-treatment (visit 4); a delta value > 2.5‰ from baseline was defined as a positive result, indicating persistent H. pylori infection. To ensure accuracy, participants taking drugs that could interfere with UBT results (e.g., H2-receptor antagonists, PPIs, P-CABs, antibiotics) underwent a minimum 4-week washout period before testing. At visit 4, subjects also completed self-reported questionnaires on health behaviors. Adverse events were graded according to the Common Terminology Criteria for Adverse Events: (1) Grade 1 (mild; transient and well-tolerated); (2) Grade 2 (moderate; causing discomfort with partial interference in daily life); and (3) Grade 3 (severe; significantly interfering with daily activities)[13]. Data on TRAEs were collected through interviews with physicians and independent staff at visit 4. Drug adherence was verified by pill counts, with good compliance defined as consuming ≥ 80% of the prescribed medication.

Study endpoint

The primary endpoint was the H. pylori eradication rate, which was analyzed across three populations: Intention-to-treat (ITT), modified ITT (mITT), and per-protocol (PP). For the ITT analysis, every randomized subject who had received at least one dose of the investigational drug was included, and missing UBT follow-up results were treated as failures. The mITT analysis excluded individuals without follow-up UBT data. The PP analysis was restricted to participants who demonstrated ≥ 80% medication adherence and had no major protocol deviations. Secondary endpoints included eradication rates stratified by antibiotic resistance status, the incidence and severity of TRAEs, and overall treatment compliance.

Study sample size

A previous study in Korea reported an eradication rate of 82.8% for 14-day P-BMT as a first-line therapy[8]. Since no previous clinical data existed for PC-BMT, we hypothesized that both the 7-day and 14-day PC-BMT regimens would achieve eradication not inferior to that of the 14-day P-BMT. Using the 14-day P-BMT rate of 82.8% as a reference, and assuming an expected eradication rate of 89.6% for PC-BMT (based on the upper confidence limit of the reference study), the sample size was calculated. With a non-inferiority margin of -8%, a one-sided alpha of 2.5%, and a power of 85%, 97 subjects were required for each of the three groups (7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT). Allowing for a projected 20% dropout, 366 patients (122 per group) were ultimately recruited.

Statistical analyses

Non-inferiority was tested for the overall eradication rates. Differences in eradication rates stratified by antibiotic resistance, adverse events, and treatment compliance among the three groups were also evaluated. Continuous variables were compared among the three groups using the Kruskal-Wallis test. Categorical variables were analyzed using the χ² test or Fisher’s exact test, as appropriate. All analyses were conducted in SAS version 9.4 (SAS Institute, Cary, NC, United States); a P value below 0.05 was considered statistically significant.

RESULTS

Patient characteristics

Overall, 366 patients were enrolled in this trial, with 122 patients randomly assigned to each of the 7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT groups (Figure 2). Twelve patients were excluded: (1) 2 for protocol violations; and (2) 10 for not receiving the investigational product. Consequently, 119 patients, 118 patients, and 117 patients from the respective groups were included in the ITT analysis. Further exclusion of those with invalid UBT follow-up (n = 17), poor compliance (< 80%; n = 16), or use of contraindicated medications (n = 2) yielded mITT analysis of 113 patients, 111 patients, and 113 patients and PP analysis of 109 patients, 104 patients, and 106 patients across the three groups.

Figure 2 Flow chart showing the selection of participants for this study. IP: Investigational product; ITT: Intention-to-treat; P-BMT: Proton pump inhibitor-based bismuth-containing quadruple regimen; PC-BMT: Potassium-competitive acid blocker-based bismuth-containing quadruple regimen; PP: Per-protocol; UBT: Urea breath test.

Table 1 summarizes the baseline features. The three arms were comparable with respect to age, sex, body mass index, alcohol intake, and smoking habits. Atrophic gastritis was the predominant endoscopic finding, with no significant intergroup difference. H. pylori culture yielded positive growth in 195 patients, with tetracycline resistance observed in only one case. Among the 195 patients with successful H. pylori culture (66 patients, 67 patients, and 62 patients in the 7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT groups, respectively), the total clarithromycin resistance rate, including both single and dual resistance, was 27.3% (18/66), 29.9% (20/67), and 24.2% (15/62), respectively, with an overall rate of 27.2% (53/195). These results confirm that the study was conducted in a setting with clarithromycin resistance exceeding 15%, consistent with the study’s premise. In contrast, metronidazole resistance was common, particularly in the 14-day P-BMT group, though the intergroup variation did not reach significance. The median compliance rates were 100.0%, 100.0%, and 100.0% in the 7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT groups, respectively, with no statistically meaningful intergroup variation (P = 0.671). Poor compliance (< 80%) was observed in 3, 7, and 6 patients in the 7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT groups, respectively.

Table 1 Baseline characteristics of the participants (intention-to-treat set), n (%).

Characteristic	7-day PC-BMT (n = 119)	14-day PC-BMT (n = 118)	14-day P-BMT (n = 117)	P value
Sex (male)	68 (57.1)	61 (51.7)	57 (48.7)	0.421
Age (years), median (IQR)	58.0 (13.0)	61.0 (16.0)	60.0 (13.0)	0.271
Body mass index (kg/m2), median (IQR)	24.5 (4.5)	23.5 (3.6)	23.6 (4.8)	0.387
Alcohol	50 (42.0)	40 (33.9)	54 (46.2)	0.150
Smoking	16 (13.5)	24 (20.3)	19 (16.2)	0.359
Endoscopic findings
Chronic atrophic gastritis	93 (78.2)	88 (74.6)	90 (76.9)	0.805
H. pylori-induced gastritis	17 (14.3)	21 (17.8)	14 (12.0)	0.446
Gastric ulcer				0.780
A1-H2	7 (5.9)	7 (5.9)	4 (3.4)
S1-S2	9 (7.6)	6 (5.1)	9 (7.7)
Duodenal ulcer				0.509
A1-H2	2 (1.7)	4 (3.4)	2 (1.7)
S1-S2	6 (5.2)	8 (7.0)	12 (10.4)
Endoscopic resection of early gastric cancer or gastric adenoma	4 (3.4)	7 (5.9)	8 (6.8)	0.469
Mucosa-associated lymphoid tissue lymphoma	0 (0.0)	0 (0.0)	2 (1.7)	0.109
Antibiotic resistance of H. pylori
Cultured	66 (55.5)	67 (56.8)	62 (53.0)	0.839
Single resistance	20 (30.3)	33 (49.3)	26 (41.9)	0.081
Clarithromycin resistance	10 (15.2)	14 (20.9)	8 (12.9)	0.446
Amoxicillin resistance	1 (1.5)	3 (4.5)	2 (3.2)	0.694
Metronidazole resistance	9 (13.6)	15 (22.4)	16 (25.8)	0.210
Tetracycline resistance	0 (0.0)	1 (1.5)	0 (0.0)	> 0.999
Dual resistance	8 (12.1)	6 (9.0)	7 (11.3)	0.830
Clarithromycin and amoxicillin	8 (12.1)	4 (6.0)	6 (9.7)	0.467
Clarithromycin and metronidazole	0 (0.0)	2 (3.0)	1 (1.6)	0.537
Multiple resistance	0 (0.0)	1 (1.5)	0 (0.0)	> 0.999
Compliance (%), median (IQR)	100.0 (0.0)	100.0 (0.0)	100.0 (0.0)	0.671
Poor compliance (< 80%)	3 (2.5)	7 (5.9)	6 (5.1)	0.417

IQR: Interquartile range; H. pylori: Helicobacter pylori; P-BMT: Proton pump inhibitor-based bismuth-containing quadruple regimen; PC-BMT: Potassium-competitive acid blocker-based bismuth-containing quadruple regimen.

H. pylori eradication rate according to treatment group

The H. pylori eradication rates are summarized in Table 2. In the ITT analysis, the eradication rates were 76.5%, 78.8%, and 77.8% in the 7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT groups, respectively. Compared with the 14-day P-BMT group, the differences in eradication rates were -1.3% (95%CI: -12.0 to 9.4; P = 0.111) for the 7-day PC-BMT group and 1.0% (95%CI: -9.5 to 11.6; P = 0.047) for the 14-day PC-BMT group. The lower bounds of both confidence intervals exceeded the non-inferiority margin of -8%; therefore, non-inferiority was not demonstrated in the ITT analysis.

Table 2 Helicobacter pylori eradication rate according to the treatment group.

Analysis	7-day PC-BMT	14-day PC-BMT	14-day P-BMT	7-day PC-BMT vs 14-day P-BMT		14-day PC-BMT vs 14-day P-BMT
				Difference (95%CI)	P value	Difference (95%CI)	P value
ITT	76.5% (91/119)	78.8% (93/118)	77.8% (91/117)	-1.3% (-12.0 to 9.4)	0.111	1.0% (-9.5 to 11.6)	0.047
Modified ITT	80.5% (91/113)	83.8% (93/111)	80.5% (91/113)	0% (-10.3 to 10.3)	0.064	3.3% (-6.8 to 13.3)	0.014
Per-protocol	81.7% (89/109)	87.5% (91/104)	79.3% (84/106)	2.4% (-8.2 to 13.0)	0.027	8.3% (-1.8 to 18.3)	0.001

Non-inferiority margin of -8%. ITT: Intention-to-treat; P-BMT: Proton pump inhibitor-based bismuth-containing quadruple regimen; PC-BMT: Potassium-competitive acid blocker-based bismuth-containing quadruple regimen.

In the mITT analysis, the eradication rates were 80.5%, 83.8%, and 80.5% in the 7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT groups, respectively. The difference between the 14-day PC-BMT and 14-day P-BMT groups was 3.3% (95%CI: -6.8 to 13.3; P = 0.014), confirming non-inferiority as the lower bound exceeded -8%. Conversely, the 7-day PC-BMT vs 14-day P-BMT difference was 0.0% (95%CI: -10.3 to 10.3; P = 0.064), failing to meet the predefined non-inferiority criterion.

In the PP analysis, the eradication rates were attained at 81.7%, 87.5%, and 79.3% in the 7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT groups, respectively. The 7-day PC-BMT group showed a difference of 2.4% compared with the 14-day P-BMT group (95%CI: -8.2 to 13.0; P = 0.027), which did not meet the non-inferiority criterion. In contrast, the 14-day PC-BMT arm achieved a difference of 8.3% (95%CI: -1.8 to 18.3; P = 0.001), thereby establishing non-inferiority.

H. pylori eradication rate according to antibiotic resistance status

The eradication rates according to the antibiotic resistance status in the PP set are summarized in Table 3. Among patients with single-resistant strains, eradication was achieved in 81.3% (13/16), 89.7% (26/29), and 87.0% (20/23) of patients in the 7-day PC-BMT, 14-day PC-BMT, and 14-day P-BMT groups, respectively, with no significant intergroup differences. There was no significant difference in eradication rates for clarithromycin-resistant strains among the three regimens: (1) 87.5% (7/8); (2) 90.9% (10/11); and (3) 87.5% (7/8). The eradication rates of the metronidazole-resistant strains were 85.7% (6/7), 93.3% (14/15), and 84.6% (11/13), with no significant intergroup differences. In the 14-day PC-BMT group, one patient with a tetracycline-resistant strain achieved successful eradication of H. pylori.

Table 3 Helicobacter pylori eradication rate according to the antibiotic resistance (per-protocol set).

Antibiotic resistance	7-day PC-BMT	14-day PC-BMT	14-day P-BMT	7-day PC-BMT vs 14-day P-BMT		14-day PC-BMT vs 14-day P-BMT
				Difference (95%CI)	P value	Difference (95%CI)	P value
Single-resistant strain	81.3% (13/16)	89.7% (26/29)	87.0% (20/23)	-5.7% (-29.3 to 17.9)	0.674	2.7% (-15.0 to 20.4)	> 0.999
Clarithromycin-resistant strain	87.5% (7/8)	90.9% (10/11)	87.5% (7/8)	0.0% (-32.4 to 32.4)	> 0.999	3.4% (-25.1 to 32.0)	> 0.999
Amoxicillin-resistant strain	0.0% (0/1)	50.0% (1/2)	100.0% (2/2)	-100.0% (-100.0 to -100.0)	0.333	-50.0% (-100.0 to 19.3)	> 0.999
Metronidazole-resistant strain	85.7% (6/7)	93.3% (14/15)	84.6% (11/13)	1.1% (-31.4 to 33.6)	> 0.999	8.7% (-14.6 to 32.0)	0.583
Tetracycline-resistant strain	N/A	100.0% (1/1)	N/A	N/A	N/A	N/A	N/A
Dual-resistant strain	75.0% (6/8)	60.0% (3/5)	100.0% (5/5)	-25.0% (-55.0 to 5.0)	0.487	-40.0% (-82.9 to 2.9)	0.444
Clarithromycin and amoxicillin	75.0% (6/8)	33.3% (1/3)	100.0% (4/4)	-25.0% (-55.0 to 5.0)	0.515	-66.7% (-100.0 to -13.3)	0.143
Clarithromycin and metronidazole	N/A	100.0% (2/2)	100.0% (1/1)	N/A	N/A	N/A	> 0.999
Multiple-resistant strain	N/A	100.0% (1/1)	N/A	N/A	N/A	N/A	N/A
No antibiotic-resistant strain	80.0% (28/35)	91.3% (21/23)	82.1 % (23/28)	-2.1% (-21.6 to 17.3)	0.830	9.2% (-9.1 to 27.4)	0.436
Culture no growth	84.0% (42/50)	87.0% (40/46)	72.0% (36/50)	12.0% (-4.1 to 28.1)	0.148	15.0% (-0.9 to 30.8)	0.083

N/A: Not applicable; P-BMT: Proton pump inhibitor-based bismuth-containing quadruple regimen; PC-BMT: Potassium-competitive acid blocker-based bismuth-containing quadruple regimen.

Among patients with dual resistance, the eradication rates were 75.0% (6/8), 60.0% (3/5), and 100% (5/5) across the three groups, respectively, with no significant differences. Similarly, in those without antibiotic resistance, the eradication rates were 80.0% (28/35), 91.3% (21/23), and 82.1% (23/28), respectively, with no significant differences between the groups. In cultures that yielded no growth, the eradication rates were 84.0% (42/50), 87.0% (40/46), and 72.0% (36/50), respectively, with no significant differences among them.

Safety

The overall incidence of adverse events is summarized in Table 4. In the ITT analysis, adverse events were reported in 23 (19.3%) in the 7-day PC-BMT group, 36 (30.5%) in the 14-day PC-BMT group, and 32 (27.4 %) patients in the 14-day P-BMT group, with a total of 34 events, 51 events, and 40 events, respectively. Although the adverse event rate was numerically lower with the 7-day regimens, the difference was not statistically significant (P = 0.145). TRAEs showed a similar pattern, occurring in 19.3%, 29.7%, and 26.5% of the patients, respectively, with no significant between-group differences (P = 0.190 and P = 0.589, respectively). No serious TRAEs were observed in the PC-BMT group. As shown in Supplementary Table 1, gastrointestinal disorders, including nausea, diarrhea, and dyspepsia, were the most common adverse events.

Table 4 Overall summary of adverse events (intention-to-treat set), n (%).

Variable	7-day PC-BMT (n = 119)		14-day PC-BMT (n = 118)		14-day P-BMT (n = 117)
	n	Frequency	n	Frequency	n	Frequency
Adverse event	23 (19.3)	34	36 (30.5)	51	32 (27.4)	40
95%CI	12.7-27.6		22.4-39.7		19.5-36.4
P value	0.145		0.594
Drug-related adverse event	23 (19.3)	34	35 (29.7)	50	31 (26.5)	39
95%CI	12.7-27.6		21.6-38.8		18.7-35.5
P value	0.190		0.589
Serious adverse event	0	0	0	0	0	0

Frequency indicates the number of adverse events. P-BMT: Proton pump inhibitor-based bismuth-containing quadruple regimen; PC-BMT: Potassium-competitive acid blocker-based bismuth-containing quadruple regimen.

DISCUSSION

The declining success rate of H. pylori eradication is a major global challenge[3]. Most international guidelines emphasize the importance of considering regional antibiotic resistance patterns when selecting eradication regimens for H. pylori[4-7]. In regions with high clarithromycin resistance (≥ 15%), BQT is recommended as the first-line regimen[4-6]. However, consensus regarding the optimal duration and composition of BQT remains lacking. In this multicenter randomized trial, the efficacy and safety of P-CAB (tegoprazan)-based BMT, which has been less extensively studied, were compared with those of conventional PPI-based BMT in Korea, a region with a high prevalence of clarithromycin resistance.

This study demonstrated that extending PC-BMT to 14 days achieved eradication efficacy and tolerability comparable to that of the conventional 14-day P-BMT regimen. Although the non-inferiority of the 14-day PC-BMT regimen was not confirmed in the ITT analysis, both the mITT and PP analyses showed comparable eradication efficacy between the 14-day PC-BMT and 14-day P-BMT regimens. Despite showing comparable eradication efficacy, the 7-day PC-BMT regimen failed to meet the predefined non-inferiority margin across all analysis sets, suggesting that shorter treatment duration may be suboptimal for H. pylori eradication. Treatment adherence exceeded 95% in all groups, and no serious TRAEs were observed. Collectively, these findings suggest that extending P-CAB (tegoprazan)-based BMT to 14 days ensures efficacy and safety comparable to those of standard PPI-based therapy, supporting its potential as a first-line treatment option in regions with high antibiotic resistance.

Effective H. pylori eradication requires appropriate antibiotic selection and potent acid suppression[14]. P-CABs, such as tegoprazan, achieve rapid, strong, and sustained suppression of gastric acid secretion compared with PPIs[11]. This enhanced acid suppression helps maintain an intragastric environment favorable to antibiotic stability and bioavailability, thereby improving the eradication efficacy of H. pylori infection. Previous studies have reported that P-CAB-based regimens achieve eradication rates comparable to or higher than those of PPI-based therapies[15,16]. The present study further supports these findings, showing that in the context of the BQT regimen, P-CAB (tegoprazan)-based BMT offers similar or superior efficacy compared with PPI-based BMT, particularly when administered for 14 days.

Among various eradication regimens, BQT is distinct because bismuth is not affected by antibiotic resistance[17]. Among the BQT regimens, BMT-based combinations have an advantage because they circumvent clarithromycin resistance, whereas extending the metronidazole duration or increasing its dosage can further help overcome metronidazole resistance[8,9,18]. In metronidazole-resistant H. pylori infections, 10-14 days of PPI-based BMT typically achieves eradication rates above 85% and is recommended as first-line therapy due to its higher eradication rates compared with the 7-day regimen[18]. However, whether a similarly extended duration is required for P-CAB-based regimens remains unclear. In this study, metronidazole resistance was identified in approximately 22% of patients. Although the number of metronidazole-resistant patients in the 7-day PC-BMT group was small, the 14-day PC-BMT regimen (94.4%) achieved a substantially higher eradication rate than the 7-day regimen (85.7%). These findings suggest that extending P-CAB-based BMT to 14 days may be beneficial for overcoming antibiotic resistance, similar to PPI-based therapy.

Current guidelines recommend that an acceptable eradication regimen should achieve at least 80% eradication in the ITT analysis and 85%-90% in the PP analysis[14]. In this study, only the 14-day P-CAB–based regimen met the guideline thresholds, whereas the 7-day P-CAB-based and 14-day PPI-based regimens did not. Recent studies in Korea have reported a gradual decline in BQT efficacy to < 90%[19,20]. Although the 14-day P-CAB-based regimen maintained acceptable eradication rates even among metronidazole-resistant strains, these findings highlight the need for optimized strategies, such as susceptibility-guided or individualized therapy, to improve treatment outcomes in regions with high antibiotic resistance.

Compliance, adverse events, and antibiotic resistance are critical determinants of successful eradication. However, BQT is associated with a relatively high incidence of adverse events[21]. In this study, the 7-day regimen showed slightly better compliance due to its shorter duration; however, overall adherence exceeded 95% across all groups, with no significant differences between them. Adverse events occurred in more than 19% of patients, with the highest incidence observed in the 14-day P-CAB-based regimen (approximately 30%). However, most of these events were mild and manageable, and no serious TRAEs were observed. These findings suggest that although a longer treatment duration may improve eradication by overcoming resistance, patient education on potential side effects and the importance of adherence remains essential to optimize treatment outcomes.

This study had several limitations. First, although it was designed as a randomized controlled trial, its open-label nature may introduce bias. Second, successful H. pylori culture was achieved in only 55% of patients, and the number of patients with dual-resistant strains was particularly small (n = 18 in total), precluding meaningful statistical comparisons of eradication efficacy in this subgroup. Future studies with larger sample sizes are needed to evaluate treatment efficacy in patients harboring dual-drug or multi-drug resistant H. pylori strains. Third, non-inferiority of the 14-day PC-BMT regimen was not confirmed in the ITT analysis, likely due to the conservative nature of this analytic approach in which missing UBT follow-up data were classified as treatment failures. However, non-inferiority was consistently demonstrated in both the mITT and PP analyses, suggesting that the ITT result reflects the impact of missing data rather than a genuine deficiency in treatment efficacy. Fourth, the eradication rates among patients without antibiotic resistance were unexpectedly low, and the reasons for this remain unclear. Possible explanations for this include biofilm formation, strain-specific distribution, niche colonization by H. pylori, and unmeasured CYP2C19 polymorphisms affecting PPI metabolism (which do not influence P-CABs) in nine studies[22-30]. Fifth, the current study used tegoprazan exclusively, and the generalizability of these findings to other P-CABs, such as vonoprazan or keverprazan, remains to be determined, as pharmacokinetic and pharmacodynamic differences among P-CABs may influence eradication outcomes. Finally, second-line treatment strategies were not comprehensively evaluated in this study; therefore, further investigation is warranted.

CONCLUSION

Fourteen-day P-CAB (tegoprazan)-based BMT demonstrated non-inferior eradication efficacy and safety, comparable to those of conventional 14-day PPI-based BMT, in mITT and PP analyses. However, non-inferiority was not confirmed in the ITT population. The 14-day PC-BMT regimen maintained high eradication rates in patients infected with metronidazole-resistant strains, supporting its use in regions with substantial antimicrobial resistance. Given the rising prevalence of clarithromycin resistance in countries with resistance rates exceeding 15% and the pharmacological advantages of P-CABs, the 14-day P-CAB (tegoprazan)-BMT regimen may be a viable treatment strategy for H. pylori eradication.