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

Study Overview
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Brief Summary
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Helicobacter pylori (H. pylori) infection is the major cause of gastritis, peptic ulcer disease, and gastric cancer in adults. 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 have declined due to increasing clarithromycin resistance. 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 adults are unknown. Moreover, the impacts on gut microbiota after H. pylori eradication should be concerned; for example, bismuth-based quadruple therapy decreases F. prausnitzii richness. The transient perturbation of the gut microbiota after H. pylori eradication were restored at 8 weeks and one year in subjects receiving clarithromycin-based triple therapy but not fully recovered in those receiving bismuth-based quadruple therapy. Therefore, the important issues are that the short-term and long-term gut dysbiosis and the recovery of gut F. prausnitzii depletion in H. pylori-infected adult patients after bismuth-based quadruple therapy. It is also uncertain the role of irreversible gut dysbiosis even though H. pylori is eradicated in gastric persist inflammation and progress to cancer, and whether probiotics could be helpful in recovering gut dysbiosis. The therapeutic strategy to eradicate H. pylori infection is based on antibiotics; however, this strategy not only increases drug resistant rates of the pathogen but also shapes the gut microbiota. 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. The investigators also hypothesize that probiotics could restore gastric or gut dysbiosis, especially gut F. prausnitzii depletion.

Detailed Description
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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.

Official Title
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The Studies of Integrating Gastric and Gut Microbiota, F. Prausnitzii Metabolites, Microenvironment, and Epigenetics to Identify the Cancer Risk of H. Pylori-related Precancerous Conditions Through an AI System and Control the Risky by Probiotic Supplements

Conditions
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Helicobacter Pylori Infection, Dysbiosis, Probiotics

Intervention / Treatment
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* Drug: Bismuth Subcitrate 120 MG Oral Tablet
* Dietary Supplement: Lactobacillus acidophilus and Bifidobacterium lactis Bb12
* Drug: Esomeprazole 40mg
* Drug: Metronidazole 250 MG
* Drug: Tetracycline Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are > 18 years Receive gastroscopy because of dyspepsia, acid regurgitation, melena, hematemesis, or others Exclusion Criteria: Bleeding diathesis, Major organic diseases Malignancy Diseases treated with chemotherapy within one month Diseases treated with steroids within one month Diseases treated with antibiotics within one month, Users of aspirin within four weeks before enrollment Users of nonsteroidal anti-inflammatory drugs within four weeks before enrollment Users of cyclooxygenase-2 selective inhibitors within four weeks before enrollment History of H. pylori eradication Ingest probiotics or probiotics-containing yogurt with a frequency of >= twice per week one month prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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. Afterward, the patients stop taking the proton pump inhibitor and antibiotics for 4 to 6 weeks, and then they receive 13C-UBT or an H. pylori stool antigen test to confirm successful eradication or not. Patients' fecal microbiota profiling is performed before and after H. pylori eradication. If patients have the depletion of gut F. prausnitzii 12 months after H. pylori eradication, they are enrolled to 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.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: The 14-day bismuth-based quadruple therapy group<br>The patients receive a 14-day course of the bismuth-based quadruple therapy, including esomeprazole (Nexium 40 mg) 1 tab twice a day, bismuth subcitrate (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. | Drug: Bismuth Subcitrate 120 MG Oral Tablet<br>* Bismuth Subcitrate (120 MG Oral Tablet) 1 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy<br>* Other names: KCB F.C.;Drug: Esomeprazole 40mg<br>* Esomeprazole (40 mg) 1 tab per oral twice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy<br>* Other names: Nexium;Drug: Metronidazole 250 MG<br>* Metronidazole (250 MG) 2 tab per oral thrice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy<br>* Other names: Tolizole;Drug: Tetracycline Pill<br>* Tetracycline (250 MG) 2 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy<br>* Other names: Tetracycline (250 mg);|
| Active Comparator: The 10-day bismuth-based quadruple therapy group<br>The patients receive a 10-day course of the bismuth-based quadruple therapy, including esomeprazole (Nexium 40 mg) 1 tab twice a day, bismuth subcitrate (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. | Drug: Bismuth Subcitrate 120 MG Oral Tablet<br>* Bismuth Subcitrate (120 MG Oral Tablet) 1 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy<br>* Other names: KCB F.C.;Drug: Esomeprazole 40mg<br>* Esomeprazole (40 mg) 1 tab per oral twice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy<br>* Other names: Nexium;Drug: Metronidazole 250 MG<br>* Metronidazole (250 MG) 2 tab per oral thrice per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy<br>* Other names: Tolizole;Drug: Tetracycline Pill<br>* Tetracycline (250 MG) 2 tab per oral four times per day for 14 days in the14-day bismuth-based quadruple therapy and for 10 days in the10-day bismuth-based quadruple therapy<br>* Other names: Tetracycline (250 mg);|
| No Intervention: The non-H. pylori-infected control<br>Age- and sex-matched patients who do not have H. pylori infection by endoscopic gastric biopsy are enrolled as the non-H. pylori-infected control. | |
| Active Comparator: The probiotic therapy group<br>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. 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). | Dietary Supplement: Lactobacillus acidophilus and Bifidobacterium lactis Bb12<br>* The probiotic powder per oral twice daily for 24 weeks. 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).<br>* Other names: President AB powder;|
| No Intervention: The non-probiotic control group<br>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 non-probiotic control therapy and they do not ingest probiotic powder. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The successful eradication rate | The patients stop taking the proton pump inhibitor and antibiotics for 4 to 6 weeks, and then they receive 13C-UBT or an H. pylori stool antigen test to confirm successful eradication or not. | About 4 to 6 weeks after receiving the H. pylori eradication regimen | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse effects and adherence to medications of the 10-day bismuth-based quadruple therapy and 14-day bismuth-based quadruple therapy groups | Secondary endpoints are the rates of adverse events and medication adherence. Adverse events and medication adherence are assessed by physicians and format questionnaire survey after completing treatment. Good adherence to medications is defined of taking >= 80% of medications. Adverse events include dizziness, skin rash, headache, unpleasant taste, abdominal pain, nausea, vomiting, diarrhea, constipation, abdominal fullness, glossitis, darkened stool, fatigue, and anorexia. Adverse events are divided into mild (no daily activity restricted) and severe (daily activity restricted or unable to work). | About 2 to 4 weeks after receiving the H. pylori eradication regimen | 
| Fecal dysbiosis and its evolution after H. pylori eradication | We compare the differences of fecal microbiota in the phylum and genus levels between the H. pylori-infected group and the non-H. pylori-infected group, especially the gut F. prausnitzii (OUT004). In addition, we plan to identify OTUs with changes in relative abundance at the genus level between the two groups by Metastats. Moreover, in the H. pylori-infected group, the evolutionary changes of fecal microbiota are compared between baseline, 2, 6, 9, and 12 months after H. pylori eradication. | Baseline, 2, 6, 9, and 12 months after receiving the H. pylori eradication regimen or after endoscopy | 
| Fecal inflammatory parameters and their evolution after H. pylori eradication | The supernatant of stool is tested by ELISA for sIgA, interleukin 6 (IL-6), IL-10, and TGF-β (Quantikine; R&D Systems, Minneapolis, MN). Fecal lactoferrin and calprotectin are measured using a commercial Leuko-Test kit (TechLab, Blacksburg, VA) and PhiCal Fecal Calprotectin Immunoassay kit (Genova Diagnostics, Asheville, NC), respectively. | 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 | Gastric fresh mucosa is biopsied for microbiota survey at surveillance endoscopy. The differences of gastric microbiota are compared at baseline and after H. pylori eradication in the H. pylori-infected group. | The patients receive surveillance endoscopy one year after H. pylori eradication | 
| Gastric precancerous conditions and the evolution after H. pylori eradication | To validate the evolution of gastric precancerous conditions, patients are divided into six groups, including normal, CGI, SPEM, stages I-II of both Operative Link for Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM), advanced stages (III-IV) of either OLGA or OLGIM, and dysplasia according to the Correa's cascade. The study plans to compare the evolution of the steps of Correa's cascade after H. pylori eradication. | About 12 months after H. pylori eradication |