Bismuth-Based Quadruple Therapy Versus Metronidazole-Intensified Triple Therapy as a First-Line Treatment for Clarithromycin-Resistant Helicobacter pylori Infection: A Multicenter Randomized Controlled Trial

Background: Clarithromycin resistance is a main factor for treatment failure in Helicobacter pylori infection. However, the treatment regimen for clarithromycin-resistant H. pylori infection has not yet been determined. Here, we aimed to compare the efficacy and cost-effectiveness of bismuth-based quadruple therapy versus metronidazole-intensified triple therapy with increased the dose and duration for clarithromycin-resistant H. pylori infection. Methods: This was a multicenter, randomized, controlled trial. A total of 782 patients with H. pylori infection examined using sequencing-based clarithromycin resistance point mutation tests were recruited between December 2018 and October 2020 in four institutions in Korea. Patients with significant point mutations (A2142G, A2142C, A2143G, A2143C, and A2144G) were randomly assigned to receive either 14-day bismuth-based quadruple therapy (n=102) or 14-day metronidazole-intensified triple therapy (n=99). Findings: The overall H. pylori eradication rate was 81.5% in the intention-to-treat analysis. The overall clarithromycin resistance rate was 25.7%. The eradication rate of 14-day bismuth-based quadruple therapy was not significantly different in the ITT analysis (80.4% vs. 69.7%, P =0.079), but was significantly higher than the 14-day metronidazole-intensified triple therapy in the per protocol analysis (95.1% vs. 76.4%, P =0.001). There were no significant differences in the incidence of side effects. Compared with empirical clarithromycin-based triple therapy, the 14-day bismuth-based quadruple therapy is more cost-effective than the 14-day metronidazole-intensified triple therapy. Interpretation: The 14-day bismuth-based quadruple therapy showed comparable efficacy with 14-day metronidazole-intensified triple therapy, and it was more cost-effective in the clarithromycin-resistant H. pylori infection. Clinical Trial Registration Details: This study was registered with the Clinical Trials Registry (NCT03431688). Funding Information: Dong-A ST. Declaration of Interests: None. Ethics Approval Statement: The study was approved by the ethics committee of four institutions, and was approved by the ethical guidelines of the Declaration of Helsinki (IRB no. 2018-01-015 for Kangdong Sacred Heart Hospital, 2018-04-007 for Hallym University Sacred Heart Hospital, 2018-04-043 for Chuncheon Sacred Heart Hospital, and 2018-11-009 for Dongtan Sacred Heart Hospital).