Rifasutenizol-based triple therapy versus bismuth plus clarithromycin-based triple therapy for first-line treatment of Helicobacter pylori infection in China (EVEREST-HP): a phase 3, multicentre, randomised, triple-dummy, double-blind, controlled, non-inferiority trial - 11/09/25

Doi : 10.1016/S1473-3099(25)00438-4

Zhiqiang Song, ProfMD ^a, Liya Zhou, ProfBM ^a,⁎ , Weihong Wang, ProfMD ^b, Cheng Lan, ProfMD ^c, Tongyu Tang, MD ^d, Jun Xie, MM ^e, Huizhen Fan, MM ^f, Xuehong Wang, ProfBM ^g, Xiuli Zuo, ProfMD ^h, Yin Zhu, ProfMD ⁱ, Chengxia Liu, ProfMD ^j, Yongsong Gu, BM ^k, Huang Feng, MD ^l, Xiang Gao, MD ^m, Qing Zhang, MD ⁿ, Hong Zhang, MD ^d, Jing Chen, MS ^o, Guozhu Geng, MD ^o, Zhenkun Ma, PhD ^o
on behalf of the
EVEREST-HP Study Group^{^†}
Members are listed at the end of the Article
Zhiqiang Song, Liya Zhou, Jing Chen, Weihong Wang, Cheng Lan, Tongyu Tang, Jun Xie, Huizhen Fan, Xuehong Wang, Xiuli Zuo, Yin Zhu, Chengxia Liu, Yongsong Gu, Huang Feng, Xiang Gao, Qing Zhang, Hong Zhang, Jianguang Xu, Qizhi Wang, Aijun Liao, Xiaojie Zhang, Chuanxin Zou, Gaifang Liu, Min Xu, Xing Li, Qin Du, Jianwei Zheng, Huixin Chen, Shaoqi Yang, Hongzhi Xu, Meihua Xu, Zhengyi Chen, Fangfang Li, Lei Chen, Zhirong Zeng, Tao Chen, Yanbo Zhen, Shiyun Tan, Xin Zeng, Hong Gao, Hong Wang, Pengyuan Zheng, Guozhu Geng, Zhenkun Ma

^a Department of Gastroenterology, Peking University Third Hospital, Beijing, China
^b Peking University First Hospital, Beijing, China
^c Hainan General Hospital, The Affiliated Hainan Hospital of Hainan Medical University, Haikou, China
^d The First Hospital of Jilin University, Changchun, China
^e First Affiliated Hospital of Gannan Medical University, Ganzhou, China
^f The People’s Hospital of Yichun City, Yichun, China
^g Qinghai University Affiliated Hospital, Xining, China
^h Qilu Hospital of Shandong University, Jinan, China
ⁱ The First Affiliated Hospital of Nanchang University, Nanchang, China
^j Binzhou Medical University Hospital, Binzhou, China
^k The People’s Hospital of Chizhou, Chizhou, China
^l The First Affiliated Hospital of Soochow University, Suzhou, China
^m The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
ⁿ The First Affiliated Hospital of Yangtze University, Jingzhou, China
^o TenNor Therapeutics, Suzhou, China

^*Correspondence to: Prof Liya Zhou, Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, ChinaDepartment of GastroenterologyPeking University Third HospitalBeijing100191China

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Thursday 11 September 2025
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Summary

Background

Rifasutenizol (TNP-2198) is a new molecular entity with a synergistic dual mechanism of action under clinical development for the treatment of Helicobacter pylori infection. We aimed to evaluate the efficacy and safety of a rifasutenizol-based triple therapy (RTT) versus bismuth plus clarithromycin-based triple therapy (BCTT) for the treatment of H pylori infection in treatment-naive patients.

Methods

EVEREST-HP was a phase 3, randomised, triple-dummy, double-blind, active-controlled, non-inferiority trial with adaptive design for sample size re-estimation conducted at 40 research hospitals in China. Treatment-naive patients aged 18–65 years, with a positive [ ¹³ C]urea breath test ([ ¹³ C]UBT), further confirmed by gastric biopsy and histological examination, were randomly assigned (1:1) to receive RTT (rifasutenizol 400 mg oral capsules, amoxicillin 1 g oral capsules, and rabeprazole 20 mg enteric-coated tables) or BCTT (bismuth potassium citrate 240 mg oral tablets, clarithromycin 500 mg oral tablets, amoxicillin 1 g oral capsules, and rabeprazole 20 mg enteric-coated tablets), all twice a day for 14 days. Randomisation was done centrally by a secure interactive web response system using block sizes of two or four and stratified by study site. RTT was compared against BCTT using a triple-dummy approach to ensure masking. The primary endpoint was H pylori eradication rate based on [ ¹³ C]UBT 4–6 weeks after the end of treatment in the modified intention-to-treat population, which included all participants who received at least one dose of the study drugs. The eradication rates of RTT and BCTT were compared using a one-sided α value of 0·025 and a non-inferiority margin of –10%. Safety endpoints included investigator assessed treatment-emergent adverse events, the severity and relationship with study drugs, findings from physical examinations, vital signs, laboratory tests, and electrocardiogram. An interim analysis was conducted by an independent data monitoring committee after 50% (350) of patients completed the last [ ¹³ C]UBT. The trial is registered with ClinicalTrials.gov , NCT05857163 .

Findings

Between May 18, 2023, and Nov 10, 2023, 1267 patients were screened and 700 patients were randomly assigned to receive either RTT (n=353) or BCTT (n=347). 261 (37%) patients were men and 439 (63%) were women. 351 patients in the RTT group and 346 in the BCTT group took at least one dose of the study drugs and were included in the modified intention-to-treat group and the safety set. H pylori was successfully cultured from 579 (83%) of 697 patients. 236 (41%) of 579 patients had H pylori infection resistant to clarithromycin, 395 (68%) to metronidazole, 203 (35%) to levofloxacin, and 47 (8%) to amoxicillin. All H pylori clinical isolates were susceptible to rifasutenizol. In the modified intention-to-treat analysis, the H pylori eradication rate in the RTT group was non-inferior to that in the BCTT group (92·0% [95% CI 88·7 to 94·6; 323 of 351] vs 87·9% [83·9 to 91·1; 304 of 346]; absolute difference 4·2% [95% CI –0·3 to 8·8]). 131 (37%) of 351 patients in the RTT group and 184 (53%) of 346 in the BCTT group had treatment-emergent adverse events. Treatment-emergent adverse events occurring in more than 5% of patients in the RTT group were diarrhoea (in 24 [7%] patients), nausea (22 [6%]), and dizziness (21 [6%]), and in more than 5% of patients in the BCTT group were taste perversion (125 [36%]), nausea (21 [6%]), and diarrhoea (19 [5%]) Most of the treatment-emergent adverse events were mild or moderate in severity. No serious adverse event related to study drugs was reported.

Interpretation

As the first novel antimicrobial agent specifically developed for H pylori infection, rifasutenizol represents a promising addition to the existing options for tackling antimicrobial resistance, and RTT represents a promising first-line treatment option for H pylori infection.