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

ABSTRACT Background We compared 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 three 14‐day regimens (1:1:1 ratio): vonoprazan‐dual (VA‐dual; vonoprazan 20 mg twice daily and amoxicillin 1 g thrice daily), vonoprazan‐triple (VAC‐triple; vonoprazan 20 mg/amoxicillin 1 g/clarithromycin 500 mg 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 A total of 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 that both VA‐dual (eradication rate of 96.0%) and VAC‐triple therapies (95.9%) were noninferior 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 noninferiority (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 highly effective and noninferior 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 Chinese Clinical Trial Registry (No. ChiCTR2200056375). Registered on February 4, 2022, https://www.chictr.org.cn/showproj.aspx?proj=14131 .