Optimization of Minocycline-Containing Bismuth Quadruple Therapy for Helicobacter pylori Rescue Treatment: A Randomized Controlled Trial

Background and Aim: Minocycline-containing bismuth quadruple therapy may provide a practical option for Helicobacter pylori (H. pylori) rescue treatment when tetracycline is unavailable, yet the optimal dosing remains unclear. We aimed to compare the efficacy and safety of different doses of minocycline-containing regimens with classical tetracycline-based bismuth quadruple therapy. Methods: Refractory H. pylori–infected participants with multiple treatment-failure were randomly (1:1:1:1) allocated to receive 14-day therapy with vonoprazan 20 mg b.i.d, bismuth 220 mg b.i.d, plus tetracycline 400 mg q.i.d and metronidazole 500 mg q.i.d (BQT), or minocycline 50 mg t.i.d and metronidazole 400 mg t.i.d (VBMn3M3), or minocycline 50 mg b.i.d and metronidazole 400 mg q.i.d (VBMn2M4), or minocycline 50 mg b.i.d and metronidazole 400 mg t.i.d (VBMn2M3). Primary outcome was H. pylori eradication rate evaluated by 13C-urea breath test at least 6 weeks after the end of treatment. Results: Totally, 480 participants were randomized. Eradication rates of BQT, VBMn3M3, VBMn2M4, and VBMn2M3 were 90.0%, 92.5%, 90.8%, and 91.7% by intention-to-treat analysis; 97.3%, 97.4%, 97.3%, and 96.5% by modified intention-to-treat analysis; 98.2%, 97.4%, 97.2%, and 96.4% by per-protocol analysis. There were no statistically significant differences in eradication rates among the regimens, and noninferiority of minocycline-based regimens was confirmed (p < 0.025). Metronidazole resistance did not affect the efficacy. VBMn2M3 group achieved the lowest overall incidence of adverse events. Conclusions: Low-dose minocycline-containing quadruple therapy provided similar eradication rates, adherence, and lower adverse event rates compared with classical bismuth quadruple therapy, and may serve as a practical substitute strategy for H. pylori rescue treatment when tetracycline access is limited. Trial Registration: ClinicalTrials.gov: NCT06561711. © 2026 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.