Second Line Bismuth Containing Quadruple Therapy With Supplementary Probiotic

Study Overview
=================
Brief Summary
-----------------
This study is designed to evaluate the clinical outcome of second line Bismuth containing quadruple therapy with supplementary probiotic for Helicobacter pylori eradication

Detailed Description
-----------------
The role of Helicobacter pylori infection in the development of peptic ulcer disease and gastric cancer have been studied extensively. Eradication of H. pylori decreases the incidence of peptic ulcer and also gastric cancer. First line therapies for H. pylori eradication with PPI and antibiotic combinations considering local clarithromycin resistant rate reaching successful rates above 90%. Bismuth containing quadruple therapy (BQT), as a major choice of second line therapy, is widely prescribed but with considerable gastrointestinal side effects including diarrhea, nausea, vomiting, bloating and abdominal pain. Probiotics supplementation is defined as the adding of non-pathologic living microorgnisms. Numerous recent studies including meta-analyses and several randomized control trials revealed supplementary probiotics may improve the adverse effects and increase the successful rate of eradication therapy. Therefore, this study aim to assess the clinical impact of probiotics on Bismuth therapy and eradication of H. pylori. It's a multicentered, randomized double blind placebo-controlled trial to evaluate the clinical outcome of second line Bismuth containing quadruple therapy with supplementary probiotic for Helicobacter pylori eradication. During the study, expected 200 patients failing in first-line Bismuth therapy would be enrolled in the trial. 200 patients are divided into two groups: one group receive probiotic for treatment period and the other group receive placebo. The treatment period is designed for 56 days: Bismuth containing quadruple therapy is performed from day 1 10 and probiotic (or placebo) is taken from day 1 56. There are 5 visits for subjects to follow: day 0, day 10, day 56, 1 year and 3 years(optional). Esophagogastroduodenal scope for the pathology, H. pylori culture, susceptibility testing, genotypic resistance and virulence factors before D0. 13C-Urea breath tests are used to check Helicobacter pylori eradication on day 56, 1 year and 3 year. In addition to blood samples for general tests, stool samples would be collected on every visit to analyze gut microbiota.

Official Title
-----------------
The Effect of Supplementary Probiotic in the Dysbiosis of Gut Microbiota Caused by Second Line Bismuth Containing Quadruple Therapy in Helicobacter Pylori Eradication- A Multicentered, Randomized Double Blind Placebo-controlled Trial

Conditions
-----------------
H.Pylori Gastrointestinal Disease

Intervention / Treatment
-----------------
* Dietary Supplement: Probiotics packets
* Dietary Supplement: Placebo packets


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients older than 20 years-old underwent documented non-Bismuth containing 1st line H. pylori eradication with failure defined by positive 13C-Urea Breath Test (13C-UBT) at least 6 weeks after completion of therapy is eligible to the study. Exclusion Criteria: History of gastrectomy, surgery in the small intestine or colon History of gastric malignancy, including adenocarcinoma or lymphoma Allergic history, history of severe adverse effects or contraindication to antibiotics (Tetracycline, Metronidazole ), proton pump inhibitor, or probiotics Pregnant or lactating women Severe concurrent chronic or acute disease (e.g. renal failure, liver cirrhosis, or active malignancy) Concomitant use of clopidogrel or warfarin Recent (<4 weeks) use of antibiotics, or recent (<4 weeks) probiotic use duration >2 weeks Not able to give consent on blinding or randomizatio Not able to give consent by his or herself

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 200 patients are divided into two groups: one group receive probiotic for treatment period and the other group receive placebo. The treatment period is designed for 56 days: Bismuth containing quadruple therapy is performed from day 1 10 and probiotic (or placebo) is taken from day 1 56.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotics packets<br>Probiotics contains 450 billion colony-forming units per packet. The compositions are maltose, lactic acid bacteria and bifidobacteria blend, cornstarch, silicon dioxide. | Dietary Supplement: Probiotics packets<br>* The treatment period is designed for 56 days: Bismuth containing quadruple therapy is performed from day 1 10 and Probiotics packets is taken from day 1 56.<br>|
| Placebo Comparator: Placebo packets<br>The compositions are maltodextrin, silicon dioxide, sucralose | Dietary Supplement: Placebo packets<br>* The treatment period is designed for 56 days: Bismuth containing quadruple therapy is performed from day 1 10 and Placebo packets is taken from day 1 56.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the incidence of adverse effects after second line BQT between probiotic group (L) and placebo group (P) according to intentional to treat (ITT) and per-protocol (PP) analyses. | Adverse events are collected | From Day 0 to Day 10. | 
| Evaluate the incidence of adverse effects after second line BQT between probiotic group (L) and placebo group (P) according to intentional to treat (ITT) and per-protocol (PP) analyses. | Adverse events are collected | From Day 0 to Day 56. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Eradication rate of second line BQT between two groups | 13C-Urea breath tests are performed to check the eradication of Helicobacter pylori between two groups | From Day 0 to Day 56. | 
| Dynamic changes in the gut microbiota between two groups | Stool sample collection for gut microbiota analysis | Day 0. | 
| Dynamic changes in the metabolic pathway of gut microbiota between two groups | Stool sample collection for gut microbiota analysis | Day 0. | 
| Re-infection rate 1 year and 3 years after second line eradication therapy | 13C-Urea breath tests are performed to check the Helicobacter pylori infection | From Day 0 to Day 56. | 
| Changes in the parameters of metabolic syndrome between two groups | Blood samples are collected for glucose, insulin, HbA1c, and lipid profiles, liver function tests, renal function tests as well as CRP. Also, transabdominal sonography for fatty liver severity assessment would be performed. | Day 0. | 
| Eradication rate of second line BQT between two groups | 13C-Urea breath tests are performed to check the eradication of Helicobacter pylori between two groups | From Day 0 to 1 year. | 
| Eradication rate of second line BQT between two groups | 13C-Urea breath tests are performed to check the eradication of Helicobacter pylori between two groups | From Day 0 to 3 years. | 
| Dynamic changes in the gut microbiota between two groups | Stool sample collection for gut microbiota analysis | Day 10. | 
| Dynamic changes in the gut microbiota between two groups | Stool sample collection for gut microbiota analysis | Day 56. | 
| Dynamic changes in the gut microbiota between two groups | Stool sample collection for gut microbiota analysis | 1 year. | 
| Dynamic changes in the gut microbiota between two groups | Stool sample collection for gut microbiota analysis | 3 years. | 
| Dynamic changes in the metabolic pathway of gut microbiota between two groups | Stool sample collection for gut microbiota analysis | Day 10. | 
| Dynamic changes in the metabolic pathway of gut microbiota between two groups | Stool sample collection for gut microbiota analysis | Day 56 . | 
| Dynamic changes in the metabolic pathway of gut microbiota between two groups | Stool sample collection for gut microbiota analysis | 1 year . | 
| Dynamic changes in the metabolic pathway of gut microbiota between two groups | Stool sample collection for gut microbiota analysis | 3 years. | 
| Re-infection rate 1 year and 3 years after second line eradication therapy | 13C-Urea breath tests are performed to check the Helicobacter pylori infection | From Day 0 to 1 year. | 
| Re-infection rate 1 year and 3 years after second line eradication therapy | 13C-Urea breath tests are performed to check the Helicobacter pylori infection | From Day 0 to 3 years. | 
| Changes in the parameters of metabolic syndrome between two groups | Blood samples are collected for glucose, insulin, HbA1c, and lipid profiles, liver function tests, renal function tests as well as CRP. Also, transabdominal sonography for fatty liver severity assessment would be performed. | Day 56. | 
| Changes in the parameters of metabolic syndrome between two groups | Blood samples are collected for glucose, insulin, HbA1c, and lipid profiles, liver function tests, renal function tests as well as CRP. Also, transabdominal sonography for fatty liver severity assessment would be performed. | 1 year. | 
| Changes in the parameters of metabolic syndrome between two groups | Blood samples are collected for glucose, insulin, HbA1c, and lipid profiles, liver function tests, renal function tests as well as CRP. Also, transabdominal sonography for fatty liver severity assessment would be performed. | 3 years. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
supplementary pylori, Bismuth quadruple therapy, H. pylori eradication