Vonoprazan Dual or Triple Therapy Versus Bismuth-Quadruple Therapy as First-Line Therapy for Helicobacter Pylori Infection: A Three-Arm, Randomized Clinical Trial

Background: We aimed to compare efficacy of vonoprazan-dual or triple therapies and bismuth-quadruple therapy for treatment-naive Helicobacter pylori (HP) infection in Southern China, where primary resistance rates of clarithromycin and levofloxacin are >30%.Methods: This was an investigator-initiated, three-arm, randomized clinical trial in Southern China. Between March 2022 and August 2023, treatment-naïve HP-infected adults were randomly assigned to receive one of the three 14-day regimens (1:1:1 ratio): vonoprazan-dual (VA-dual; vonoprazan 20mg twice daily and amoxicillin 1g thrice daily), vonoprazan-triple (VAC-triple; vonoprazan 20mg/amoxicillin 1g/clarithromycin 500mg twice daily), or bismuth-quadruple therapy containing bismuth, esomeprazole, tetracycline and metronidazole. Primary outcome was noninferiority in HP eradication, evaluated by UBT 4-6 weeks post-treatment by intention-to-treat (ITT) and per-protocol (PP) analysis (based on subjects who completed 14-day treatment and rechecked UBT). Bonferroni-adjusted p-value of <0.017 was used to determine statistical significance.Results: 298 subjects (mean age:35.7±8.4 years; male:134 [45.0%]; VC-dual:100, VAC-triple:98, bismuth-quadruple:100) were enrolled, and 292 (98.0%) had UBT rechecked. ITT analysis showed both VA-dual (eradication rate of 96.0%) and VAC-triple therapies (95.9%) were non-inferior to bismuth-quadruple therapy (92.0%) (difference:4.0%, 95% CI:-2.9% to 11.5%, p<0.001; and 3.9%, 95% CI:-3.1% to 11.5%, p<0.001, respectively). PP analysis also revealed non-inferiority (96.7% or 96.7% vs 97.4%, with difference:-2.9% and -2.9%, p=0.009 and 0.010, respectively). The frequency of adverse events was 39.0%, 56.1% and 71.0% in VA-dual, VAC-triple and bismuth-quadruple therapies, respectively.Conclusions: VA-dual and VA-triple therapies are non-inferior to bismuth-quadruple therapy in Southern China. Given the lower adverse effects and fewer antibiotic use, VA-dual therapy is the preferred first-line treatment for HP infection.Trial Registration: This was an investigator-initiated, three-arm, single-center RCT in Shenzhen, China and was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) with the trial registration number ChiCTR2200056375.Funding: This study was supported by the Health Commission Grant of Guangdong Province, China (ref. no. B2021239) and the Shenzhen Science and Technology Program (Grant No. JCYJ20230807113503006).Declaration of Interest: The authors declare that they have no competing interestsEthical Approval: The study protocol was in accordance with the Declaration of Helsinki and approved by the Medical Ethics Committee of the University of Hong Kong-Shenzhen Hospital (approval number: [2022] 015). Written informed consent was sought from all study participants.