The Efficacy of 10-day and 14-day Bismuth-based Quadruple Therapy in First-line H. Pylori Eradication

Bismuth-based quadruple therapy is recommended by a recent review to be the first-line treatment for H. pylori eradication, replacing clarithromycin-based triple therapy. It is because the eradication rates of triple therapy in adults and clarithromycin-contained sequential therapy in children have declined due to increasing clarithromycin resistance in both adults and children. The best regimen for H. pylori eradication should be the one which succeeds on the first attempt. However, the effectiveness and the optimal duration of bismuth-based quadruple therapy for first-line H. pylori eradication in children and adults, respectively, are unknown. Moreover, the impacts on gut microbiota after H. pylori eradication should be concerned; nevertheless, the results are controversial.

Probiotic supplements are beneficial to gut health through modulation of the gut microbiota and metabolomics. Our previous studies also reported that the efficacy of H. pylori eradication is improved and relevant immune response could be modified by probiotics-containing yogurt ingestion. Our preliminary data have shown that gut F. prausnitzii depletion in H. pylori-infected children could be reversed after triple eradication therapy with probiotics-containing yogurt ingestion. However, it is uncertain whether the recovery of gut F. prausnitzii by probiotics could restore gut dysbiosis or improve systemic inflammation, and the role of gut F. prausnitzii or metabolites in the H. pylori-microbiota-host metabolism axis.

The investigators hypothesize that bismuth-based quadruple therapy could be an optimal regimen for first-line H. pylori eradication in the era of increasing clarithromycin resistance; moreover, gut dysbiosis could be reversed after bismuth-based quadruple therapy. Furthermore, the efficacy of the10-day course is not inferior to that of the 14-day course in H. pylori eradication. Among the H. pylori-infected patients, they are randomized to the 14-day bismuth-based quadruple therapy group and the 10-day bismuth-based quadruple therapy group to receive a 14-day and 10-day course, respectively, of the bismuth-based quadruple therapy, including esomeprazole (Nexium 40 mg) 1 tab twice a day, dibismuth trioxide (KCB F.C. 120 mg) 1 tab four times a day, metronidazole (Flagyl 250 mg) 2 tab thrice a day, and tetracycline (250 mg) 2 tab four times a day.

Moreover, the investigators also hypothesize that probiotics could restore gastric or gut dysbiosis, especially gut F. prausnitzii depletion. The patients who still have depletion of gut F. prausnitzii 12 months after H. pylori eradication are enrolled into the probiotic supplement trial. They are randomized to the probiotic therapy group ingesting probiotic powder twice daily for 24 weeks and the non-probiotic control group, respectively. The probiotic powder is named as "President AB powder", which contains an approximately equal mixture of Lactobacillus acidophilus and Bifidobacterium lactis Bb12 at a concentration of \>= 10E9 CFU/mL (President Corp., Tainan, Taiwan)

Sample size assessment: The investigators propose that the eradication rates in the bismuth-based quadruple therapy are \~97%. The case ratio of the two groups is 1:1. If there is a true difference in favor of the 14-day bismuth-based quadruple therapy of 7% (10-day therapy vs. 14-day therapy, \< 90% vs. 97%), then a total of 250 patients are required to be 90% (power) sure that the upper limit of a one-sided 97.5% confidence interval (or equivalently a 95% two-sided confidence interval) will exclude a difference in favor of the 14-day bismuth-based quadruple therapy group of more than 7% \[Sealed Envelope Ltd. 2012. Power calculator for binary outcome non-inferiority trial. \[Online\] Available from: https://www.sealedenvelope.com/power/binary-noninferior/ \[Accessed Sun Feb 14 2021\]. Assuming a surveying failure rate of \~20%, at least 312 patients are needed.

In addition, the investigators propose that the rates of gut F. prausnitzii depletion before and after probiotic therapy are 50% and 25%, respectively. With a two-side alpha value of 0.05 and power of 80% (β=0.20), the number of patients required is 92 in such a paired sample. Assuming a surveying failure rate of 10%, at least 103 subjects are needed in the probiotic therapy group. Moreover, according to case ratio of the probiotic therapy group and the non-probiotic control group as 7:3, and the number required is 46 in the non-probiotic control group.

Statistical analysis: The statistical analysis is performed with SPSS software (SPSS 17, Chicago, IL, USA). The Student's t-test, Pearson's χ2 test, and Mann-Whitney U test are conducted to identify the statistical differences between the two comparison groups. One-way ANOVA with Tukey's least significant difference, Pearson's χ2 test, and Kruskal-Wallis one-way ANOVA by ranks and post hoc comparison by Mann-Whitney U test are used to identify the statistical differences between the three or more comparison groups. Paired t-test, McNemar, and Wilcoxon signed-rank test are conducted to identify the statistical differences between the pair data. All of the tests are two-tailed with the statistical significance defined as P \< 0.05.

• Adverse effects and adherence to medications of the 10-day bismuth-based quadruple therapy and 14-day bismuth-based quadruple therapy groups [Срок оценки: About 2 to 4 weeks after receiving the H. pylori eradication regimen]
• Fecal microbiota and metabolites and the microbial evolution after H. pylori eradication [Срок оценки: Baseline, 6-12 months after receiving the H. pylori eradication regimen or after endoscopy]
• Fecal inflammatory parameters and their evolution after H. pylori eradication [Срок оценки: Baseline, 2, 6, 9, and 12 months after receiving the H. pylori eradication regimen or after endoscopy]
• Gastric microbiota and its evolution after H. pylori eradication [Срок оценки: The patients receive surveillance endoscopy one year after H. pylori eradication]
• Gastric precancerous conditions and the evolution after H. pylori eradication [Срок оценки: About 12 months after H. pylori eradication]