Tegoprazan and low- or high-dose amoxicillin dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori eradication (TREAT): protocol for a multicenter,open-label,non-inferiority,randomized controlled trial

Abstract

Background:

Recently, tegoprazan was widely used for the treatment of acid-related diseases, including Helicobacter pylori (H. pylori) infection. However, the optimized parameters of tegoprazan and amoxicillin used in dual therapy for eradicating H. pylori remained unresolved.

Objectives:

We mainly aim to compare the efficacy and safety of 14-day tegoprazan and low-dose amoxicillin dual therapy (LTA) or high-dose amoxicillin dual therapy (HTA) with 14-day bismuth-containing quadruple therapy (BQT) as first-line treatment of H. pylori infection. The antibiotic resistance and the impacts of therapy on gut microbiota are also evaluated.

Design:

Study protocol for a multicenter, open-label, non-inferiority, randomized controlled trial.

Methods and analysis:

This trial will recruit H. pylori-infected individuals aged 18–70 years without previous eradication. Participants will be randomized in a 1:1:1 ratio to LTA (amoxicillin 1 g twice a day and tegoprazan 50 mg three times daily), HTA (amoxicillin 1 g and tegoprazan 50 mg both three times daily), or BQT (amoxicillin 1 g, clarithromycin 500 mg, esomeprazole 20 mg, and bismuth potassium citrate 220 mg all twice daily) for 14 days using block size of 6. Stool samples will be collected at baseline to detect antibiotic resistance and at baseline, week 2, and weeks 8–10 to evaluate the alteration of gut microbiota. The primary outcome is the eradication rate of H. pylori, assessed by ¹³C urea breath test, in intention-to-treat, modified intention-to-treat, and per-protocol analyses. Secondary outcomes include adverse events, adherence, antibiotic resistance, and alterations to the gut microbiota.

Ethics:

This study has been approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (No. 2024150-2). Ethics approval of each participating center is required before initiation of enrollment. Written informed consent to participate will be obtained from all participants.

Discussion:

This is the first study to investigate the safety and efficacy of 14-day tegoprazan with different dosages of amoxicillin therapies in comparison with BQT. The outcomes of this study will optimize the use of tegoprazan dual therapy for H. pylori eradication.

Trial registration:

The trial was registered on the Chinese Clinical Trial Registry (ChiCTR2400089979) on 20th September 2024.

Keywords

bismuth-containing quadruple therapy dual therapy tegoprazan

Introduction

Helicobacter pylori (H. pylori), infecting approximately 43% of the global population,¹ is a major etiological agent of gastrointestinal disorders, including peptic ulcers, gastric mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma.^2–4 Consequently, H. pylori eradication is an effective way to prevent the incidence or progression of gastric diseases, particularly for gastric cancer. Recent international consensus reports recommended that all infected individuals should receive eradication unless competing factors existed.⁴

For decades, bismuth-containing quadruple therapy (BQT) has been recommended as the first-line treatment for H. pylori infection,^4,5 achieving acceptable efficacy, especially for strains with clarithromycin resistance.^6–8 However, its application is constrained by multiple challenges in China: sensitive antibiotics (furazolidone or tetracycline) are unavailable in a subset of regions, complicated administration leads to poor compliance for part of individuals, existing adverse effects contribute to discontinue of treatment especially for elder patients.⁹ Considering China is a country with high incidence of gastric cancer, high prevalence of individual and familial-based H. pylori infection and high resistance rate of antibiotics, optimized regimen with high efficacy, minimal use of antibiotics, and fewer side effects are required for eradicating H. pylori.

Potent intragastric acid suppression is the key for H. pylori eradication because elevated gastric pH enhances replicated bacterial susceptibility to antibiotics and stabilizes acid-labile antibiotics (amoxicillin etc.).⁵ Potassium-competitive acid blockers (P-CABs), through reversible and selective inhibition of H⁺/K⁺-ATPase,¹⁰ show pharmacodynamic advantages than proton pump inhibitors (PPIs), including rapid onset, sustained suppression of gastric acids, and are not influenced by CYP2C19 polymorphism.^11,12 P-CABs, represented by vonoprazan, have shown satisfactory efficacy in the eradication of H. pylori.¹³ Our previous systematic review and meta-analysis included 15 studies showing that the eradication rate of vonoprazan and amoxicillin dual therapy was 85.0% in intention-to-treat (ITT) analysis and 90.0% in per-protocol (PP) analysis.¹⁴ Tegoprazan, a novel P-CAB, demonstrates significantly faster absorption than vonoprazan^15–17 (the median T_max of 0.5–1 h for tegoprazan and 1.5–4 h for vonoprazan) and achieves peak gastric pH elevation within 1 h post-dose.¹⁸ However, the shorter elimination half-life of tegoprazan^16,17 (3.87–4.57 h vs 9 h for vonoprazan) and lower pKa^16,19 (5.1 vs 9.3) limit its ability to sustain pH > 6.0 beyond 12 h, which is critical for the efficacy of amoxicillin. Thus, while the rapid acid suppression of tegoprazan is advantageous, its pharmacokinetic profile necessitates optimized dosing strategies. Notably, while TPZ-based regimens have demonstrated preliminary efficacy,^20–22 no multicenter trial has evaluated whether increasing dosing frequency (e.g., three times daily) can compensate for the abbreviated duration of acid suppression by tegoprazan and directly compared the efﬁcacy of tegoprazan with low-dose amoxicillin and high-dose amoxicillin dual therapy for eradicating H. pylori.

Objectives

The objectives of this study are to compare the efficacy and safety of 14-day tegoprazan-based dual therapy with different doses of amoxicillin versus BQT, detect the resistance rate of antibiotics, and assess the short-term effects of therapy on the gut microbiota.

Methods and analysis

Trial design

This TREAT (tegoprazan and low- or high-dose amoxicillin dual therapy versus bismuth-containing quadruple therapy for helicobacter pylori eradication) trial is an investigator-initiated, multicenter, open-label, non-inferiority, randomized controlled trial. The overall flowchart of the study is shown in Figure 1. This trial protocol was written in accordance with the Standard Protocol Items: Recommendation for Intervention Trial (SPIRIT) guideline.²³

Figure 1.

The overall flowchart of the TREAT study.

Eligibility criteria

The inclusion criteria are as follows: (1) aged 18–70 years; (2) H. pylori-infected subjects without eradication history; (3) the confirmation of H. pylori-infection evaluated by positive ¹³C urea breath test (¹³C-UBT) above 6; and (4) signed informed consent.

The exclusion criteria are as follows: (1) allergy to amoxicillin, clarithromycin, tegoprazan, esomeprazole, or bismuth; (2) severe gastric diseases (gastric cancer, gastrointestinal bleeding, etc.) found by endoscopy; (3) history of gastric surgery; (4) more than 2 peptic ulcers or ulcer diameters > 0.5 cm; (5) serious illness (neurological, cardiovascular, pulmonary, renal, endocrinological or hematological disorders, etc.); (6) pregnancy or breast feeding; (7) PPI or antibiotics use within 1 month before enrollment; (8) participation in other studies within 1 month before enrollment; and (9) not willing to participate in the study.

Study population and centers

In this multicenter randomized controlled trial, all individuals infected with H. pylori without an eradication history will be screened by the independent researchers. After signing the informed consent, study participants meeting all the eligibility criteria will be randomized. All the data stored in the electronic database is de-identified to guarantee patients’ privacy.

We plan to recruit participants from the following eight centers: The First Affiliated Hospital of Nanchang University, Shanghai Changhai Hospital, Beijing Friendship Hospital, Nanjing First Hospital, The Third Xiangya Hospital, Xi’an Central Hospital, Shenzhen University General Hospital, and The Third People’s Hospital of Jingdezhen. The trial will use competitive enrollment, and it is estimated that a period of 6–12 months will be necessary to complete the enrollment process (Supplemental Material).

Randomization, allocation, and blinding

Eligible participants with H. pylori infection will be randomized into one of three treatment arms: 14-day tegoprazan and low-dose amoxicillin (LTA), high-dose amoxicillin dual therapy (HTA), or 14-day bismuth-containing quadruple therapy (BQT). The LTA dual therapy consists of amoxicillin 1 g twice daily and tegoprazan 50 mg three times daily, the HTA dual therapy consists of amoxicillin 1 g and tegoprazan 50 mg both three times daily, and BQT consists of esomeprazole 20 mg twice daily, bismuth potassium citrate 220 mg twice daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily. Tegoprazan, esomeprazole, and bismuth were taken orally 30 min before meals, while amoxicillin and clarithromycin were administered 30 min after meals. Stool samples were collected at baseline (before treatment), week 2 (after eradication), and week 8–10 (conﬁrmation of H. pylori status) to assess the short-term effects of therapy on the gut microbiota, and the stool samples were collected at baseline to detect clarithromycin and levofloxacin resistance.

The study drug information is as follows: tegoprazan (50 mg/tablet, Shandong Luoxin Pharmaceutical Group Co. Ltd), esomeprazole (20 mg/tablet, AstraZeneca Pharmaceutical Co. Ltd), amoxicillin (250 mg/tablet, Zhuhai United Pharmaceutical Co. Ltd), clarithromycin (500 mg/tablet, Abbott Laboratories Co. Ltd), and bismuth potassium citrate (110 mg/tablet, Livzon Pharmaceutical Group Inc.).

Permuted block randomization with a block size of six, stratified by the participating sites, will be performed using a central randomization website (capctg.medbit.cn) that was secure, encrypted, and password-protected. Participants and investigators will not be blinded to the study. However, the trial statistician will be blinded to patient allocation.

Sample size calculation

In previous studies, eradication rates of HTA dual therapy for H. pylori treatment were between 88.3 and 93.81%.^9,22 We assumed that H. pylori eradication rates of LTA, HTA, and BQT for 14 days were 90%. Assuming a power of 0.80, an α (one-sided) of 0.025, and a follow-up loss rate of 10%, the non-inferiority trial requires a sample size of 474 participants (158 in each group). The sample was calculated using the PASS software (PASS version 11.0.7).

Outcome measurement

The primary outcome of this study is the H. pylori eradication rate, assessed by ITT, modified ITT (mITT), and PP analyses. The ITT population includes all randomly assigned participants. Patients who do not visit for follow-up of ¹³C-UBT will be considered failures of treatment. The mITT population includes individuals who received at least one dose of medication and completed ¹³C-UBT. The PP population includes individuals who complete follow-up, take at least 80% of their allocated drugs, and complete ¹³C-UBT. The secondary outcomes include the adverse events, adherence, clarithromycin and levofloxacin resistance, and the alterations of gut microbiota induced by each therapy. All participants will be informed about potential treatment-related adverse events, and treatment-related adverse events will be recorded during the telephone interview on day 7 or 14 after enrollment (completion of eradication regimen). The severity of the adverse events will be classified into three levels: mild (transient and well-tolerated), moderate (causing discomfort and partially interfering with daily activities), and severe (causing considerable interference with daily activities). Participants who receive at least one dose of the study drug are included in the analysis of treatment-emergent adverse events.

Data collection and management

A web-based electrical database (Unimed Scientific, Wuxi, China) will be utilized for the data collection and storage. All data will be input by the nominated investigators (one or two in each participating center), who will be trained for data entry conducted by the central site (The First Affiliated Hospital of Nanchang University). To maintain patient confidentiality, all data stored in the electronic database will be de-identified. Before statistical analysis, all data will be securely locked. The schedule of enrollment and assessments is shown in Table 1.

Table 1.

The protocol schedule and procedures.

Assessment	Pre-study screening	Baseline	Treatment period	Follow-up period
Inclusions/exclusion criteria	X
Informed consent	X
Collection of data on demographics	X
Medical history	X
Clinical symptoms	X
¹³C-urea breath test	X			X
Informed consent form		X
Randomization		X
Stool samples		X	X	X
Drug compliance			X
Adverse events			X	X

Statistical analysis

We will evaluate and compare the H. pylori eradication rate of the non-inferiority trial of the three groups using two-sided 95% CI and hypothesis testing (one-sided z-test). Pearson’s χ² test and Student’s t-test will be used to analyze differences in categorical and continuous variables between groups, respectively. All tests of signiﬁcance are two-tailed except the one-sided z-test of non-inferiority, and p < 0.05 was considered to indicate a signiﬁcant difference. All statistical computations will be carried out using SPSS (version 25.0) or SAS (version 9.4), and bioinformatics of the gut microbiome will be performed using R software (version 3.6.1).

Discussion

In China, BQT has been widely recommended as a first-line regimen for H. pylori eradication. The 2022 Chinese national clinical practice guideline on H. pylori eradication treatment recommends five bismuth-containing quadruple regimens,²⁴ and our study uses amoxicillin and clarithromycin, one of these five antibiotic combinations, with PPI and bismuth as the control group. Antibiotic resistance is one of the main factors affecting the efﬁcacy of H. pylori regimens, and our previous multicenter study showed that the resistance rate of H. pylori to metronidazole, clarithromycin, and levofloxacin had exceeded the warning line (15.0%).^25,26 Urgent alternative regimens with high efficacy and unnecessary antibiotic use are needed.

Recent regional multicenter trials^9,21 completed in China showed that tegoprazan (50 mg twice daily) and amoxicillin (1000 mg three times daily) dual therapy for 14 days failed to achieve an eradication rate above 90% by PP analysis, although dual therapy containing tegoprazan showed similar efficacy with bismuth-containing quadruple therapy. Another multicenter study²² also evaluated the efficacy of amoxicillin (1000 mg three times daily) with different dosages of tegoprazan (50 mg once or twice daily) for eradicating H. pylori, showing that tegoprazan-based therapy achieved eradication rate above 85% by ITT analysis and 90% by PP analysis, as well as fewer adverse events compared to bismuth-containing quadruple therapy. However, this is a regional multicenter study with a limited sample size. In our previous multicenter study,²⁵ we confirmed that the most important parameter in dual therapy for eradicating H. pylori is the elevated gastric pH induced by P-CAB, followed by the dosage or frequency of amoxicillin. A phase I, randomized, double-blind, and placebo-controlled clinical trial of tegoprazan reported that tegoprazan used as 100 mg daily could produce more rapid suppression of gastric acids than esomeprazole 40 mg on day 1, but showed similar ability on day 7.¹⁸ Esomeprazole was recommended to be used at a high dose in dual therapy.^4,24 Considering tegoprazan used as 50 mg four times daily is not convenient, we plan to increase the dosage of tegoprazan from 50 mg twice to three times daily to evaluate whether the efficacy of tegoprazan-based dual therapy could be increased.

This multicenter, open-label, non-inferiority, randomized controlled trial aims to compare the efficacy and safety of 14-day tegoprazan–amoxicillin dual therapy (low-dose vs high-dose amoxicillin) and BQT for eradicating H. pylori. The results obtained from this study have the potential to optimize the essential parameters of tegoprazan–amoxicillin dual therapy for eradicating H. pylori in China.

Supplemental Material

sj-docx-1-tag-10.1177_17562848251366374 – Supplemental material for Tegoprazan and low- or high-dose amoxicillin dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori eradication (TREAT): protocol for a multicenter, open-label, non-inferiority, randomized controlled trial

Supplemental material, sj-docx-1-tag-10.1177_17562848251366374 for Tegoprazan and low- or high-dose amoxicillin dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori eradication (TREAT): protocol for a multicenter, open-label, non-inferiority, randomized controlled trial by Yi Hu, Xin Xu, Cong He, Nian-Shuang Li, Yong Xie, Xu Shu, Nong-Hua Lu and Yin Zhu in Therapeutic Advances in Gastroenterology

Footnotes

Acknowledgements

This work was supported by the Key Laboratory Project of Digestive Diseases in Jiangxi Province (2024SSY06101). We would like to acknowledge all the patients and clinical staff who participated in the TREAT study.

Declarations

ORCID iDs

Xu Shu

Yin Zhu

Supplemental material

Supplemental material for this article is available online.

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