Clinical trial NCT04527055: The Efficacy of 10-day and 14-day Bismuth-based Quadruple Therapy in First-line H. Pylori Eradication
Official title: 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
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE4
Conditions: Helicobacter Pylori Infection
Dysbiosis
Probiotics
Lead sponsor: National Cheng-Kung University Hospital
Sponsor class: OTHER
First posted: 2020-08-26
Enrollment: 312
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: The successful eradication rate
timeFrame: About 4 to 6 weeks after receiving the H. pylori eradication regimen
Secondary outcomes:
measure: Adverse effects and adherence to medications of the 10-day bismuth-based quadruple therapy and 14-day bismuth-based quadruple therapy groups
timeFrame: About 2 to 4 weeks after receiving the H. pylori eradication regimen
measure: Fecal microbiota and metabolites and the microbial evolution after H. pylori eradication
timeFrame: Baseline, 6-12 months after receiving the H. pylori eradication regimen or after endoscopy
measure: Fecal inflammatory parameters and their evolution after H. pylori eradication
timeFrame: Baseline, 2, 6, 9, and 12 months after receiving the H. pylori eradication regimen or after endoscopy
measure: Gastric microbiota and its evolution after H. pylori eradication
timeFrame: The patients receive surveillance endoscopy one year after H. pylori eradication
measure: Gastric precancerous conditions and the evolution after H. pylori eradication
timeFrame: About 12 months after H. pylori eradication
Other outcomes:
Locations:
city: Tainan
country: Taiwan
facility: Helicobacter pylori study group, National Cheng Kung University Hospital
Study officials:
affiliation: National Cheng-Kung University Hospital
name: Hsiu-Chi Cheng, PhD
role: PRINCIPAL_INVESTIGATOR
References: