Helicobacter Pylori Eradication Therapy in Portugal

Study Overview
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Brief Summary
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Helicobacter pylori (H. pylori) infection remains a major public health problem, with an estimated prevalence of over 50% worldwide and 60-86% for Portugal. H. pylori is associated with significant morbidity and mortality from peptic ulcerative disease to gastric cancer, whose eradication therapy has proven to be effective in preventing these complications. Factors involved in the development of these conditions include H. pylori virulence, host genetic factors and gut microbiota. Given the increasing pattern of antibiotic resistance evidenced by this bacterium and the scarcity of available antibiotic therapy, both in Portugal and worldwide, there is not enough evidence on the best eradication strategy. Regarding the uncertainties about the potential negative impact of indiscriminate use of eradication therapy on gut microbiota, either by proton pump inhibitors or by antibiotics per se, there is an overriding need for evidence about the real impact of this therapy on oral or gut flora and possible clinical consequences in immunological, metabolic, nutritional and oncological terms. Objectives: Comparative evaluation of the efficacy of the different quadruple therapy regimens recommended for the H. pylori eradication. Comparative evaluation of the safety profile in terms of clinical, and immunological and gut microbiota impact of the different therapies for the H. pylori eradication.

Detailed Description
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Introduction: Helicobacter pylori (H. pylori) infection remains a major public health problem, with an estimated prevalence of over 50% worldwide and 60-86% for Portugal. H. pylori is associated with significant morbidity and mortality from peptic ulcerative disease to gastric cancer, whose eradication therapy has proven to be effective in preventing these complications. Factors involved in the development of these conditions include H. pylori virulence, host genetic factors and gut microbiota. Given the increasing pattern of antibiotic resistance evidenced by this bacterium and the scarcity of available antibiotic therapy, both in Portugal and worldwide, there is not enough evidence on the best eradication strategy. Regarding the uncertainties about the potential negative impact of indiscriminate use of eradication therapy on gut microbiota, either by proton pump inhibitors or by antibiotics per se, there is an overriding need for evidence about the real impact of this therapy on oral or gut flora and possible clinical consequences in immunological, metabolic, nutritional and oncological terms. Objectives: Comparative evaluation of the efficacy of the different quadruple therapy regimens recommended for the H. pylori eradication. Comparative evaluation of the safety profile in terms of clinical, and immunological and gut microbiota impact of the different therapies for the H. pylori eradication. Methods: Prospective longitudinal multicentre study of total of patients with gastric infection by H. pylori, diagnosed by 13C-urea breath test or histological analysis of gastric biopsies and clinical indication for its eradication, referred to the different participating Portuguese hospital units and a blind randomized controlled clinical trial of the efficacy and safety of the different quadruple therapy regimes recommended for the H. pylori eradication. This study will be carried out in 4 phases: Phase 1 - Recruitment and randomization of patients by the different quadruple eradication schemes with and without bismuth (5 parallel arms); Phase 2 - H. pylori eradication with evaluation of the efficacy and safety rates at 1 month and the absence of reinfection at 12 months after treatment and collection of stool samples before and after the eradication therapy for evaluation of changes in gut microbiota; Phase 3 - Analysis of richness, diversity and uniformity of gut microbiota by DNA sequencing using the hypervariable region of the ribosomal 16S bacteria gene as a taxonomic identification marker and their clinical impact on immunology, metabolism and nutrition at 12 months after the H. pylori eradication therapy; and Phase 4 - Analysis of immunological changes through the study of cell populations by flow cytometry (CD4+, CD8+, B-cell, T-cell, natural killer cells, cells ratio) and cytokines, chemokines and growth factors by xMAP/Luminex before and 12 months after the H. pylori eradication therapy. Expected results, impact and scientific outputs: Given the high rate of triple therapy inefficacy, high antibiotic resistance and the scarcity and controversy of existing literature on quadruple regimens, there may be relevant differences in the approved quadruple regimens for the H. pylori eradication, being necessary to define which is the most effective and safe in Portugal, decreasing the rate of ineffectiveness and exposure to multiple antibiotics. The homeostasis of gut microbiota is significantly changed after H. pylori eradication and this modification may be substantially different according to the therapeutic scheme used, with clinical implications on immunology, metabolism and nutrition. Thus, a randomized trial to compare quadruple regimens is need, allowing in the future, an individualized selection of the H. pylori eradication regimen, taking into account the higher efficacy and safety and lower gut dysbiosis and its systemic consequences, in short and long term. Modulating oral and gut microbiota therapies, including prebiotics, probiotics, symbiotics, fecal microbiota transplantation and perhaps targeted-immunotherapy may be beneficial as adjuvant therapy to existing H. pylori eradication regimens, in a systematic way or for some therapeutic regimes or risk groups.

Official Title
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Helicobacter Pylori Eradication Therapy in Portugal: Prospective, Randomized, Blind and Multicentre Trial on the Efficacy of Quadruple Therapies and Their Clinical Impact, and Immunological and Gut Microbiota Changes

Conditions
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Helicobacter Pylori, Gut Microbiota, Immunology

Intervention / Treatment
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* Drug: H. pylori eradication scheme A
* Drug: H. pylori eradication scheme B
* Drug: H. pylori eradication scheme C
* Drug: H. pylori eradication scheme D
* Drug: H. pylori eradication scheme E


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gastric infection by H. pylori by histological examination of gastric biopsies or carbon 13-labeled urea breath test. Exclusion Criteria: Age < 18 years; Pregnant, breast-feeding or women of childbearing age who do not comply with effective anticonception measures; History of allergy, hypersensitivity or contraindication to the use of H. pylori eradication drugs (antibiotics or proton pump inhibitors); History of previous gastrointestinal surgery or neoplasia; Previous H. pylori eradication therapies; Antibiotic or probiotic therapies in the month prior to recruitment; Use of proton pump inhibitors, other antacids or gastric mucosal protection agents in the 2 weeks prior to recruitment; Corticosteroids or immunomodulatory therapy in the month prior to recruitment; Immunodeficiency; Insulin-treated diabetes mellitus; Obesity (Body mass index ≥30Kg/m2); Use of laxative therapy in the 15 days prior to recruitment; Decompensated heart, liver, kidney or respiratory diseases and; Refusal or inability to give informed consent.

Ages Eligible for Study
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Minimum Age: 18 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: An interventional study is proposed to compare the efficacy and safety of the different approved H. pylori eradication quadruple regimens. Patients will be randomly assigned to the five quadruple regimens arms (A, B, C D and E). All patients will be followed during 12 months. A standardized protocol will be applied for all the groups, differing only in type of quadruple regimen used.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: H. pylori eradication scheme A<br>Esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 8/8h, for 14 days | Drug: H. pylori eradication scheme A<br>* Esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 8/8h, for 14 days<br>* Other names: Concomitant bismuth-free A;|
| Experimental: H. pylori eradication scheme B<br>Esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 12/12h, for 14 days | Drug: H. pylori eradication scheme B<br>* Esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 12/12h, for 14 days<br>* Other names: Concomitant bismuth-free B;|
| Experimental: H. pylori eradication scheme C<br>Esomeprazole 40mg bid + bismuth subsalicylate 420mg 6/6h + metronidazole 375mg 6/6h + tetracycline 375mg 6/6h, for 10 days | Drug: H. pylori eradication scheme C<br>* Esomeprazole 40mg bid + bismuth subsalicylate 420mg 6/6h + metronidazole 375mg 6/6h + tetracycline 375mg 6/6h, for 10 days<br>* Other names: Concomitant with bismuth;|
| Experimental: H. pylori eradication scheme D<br>Esomeprazole 40mg bid + amoxicillin 1g 12/12h for 7 days, followed by esomeprazole 40mg bid + clarithromycin 500mg 12/12h + metronidazole 500mg 12/12h for 7 days | Drug: H. pylori eradication scheme D<br>* Esomeprazole 40mg bid + amoxicillin 1g 12/12h for 7 days, followed by esomeprazole 40mg bid + clarithromycin 500mg 12/12h + metronidazole 500mg 12/12h for 7 days<br>* Other names: Sequential;|
| Experimental: H. pylori eradication scheme E<br>Esomeprazole 40mg bid + amoxicillin 1g 12/12h for 7 days, followed by esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 12/12h for 7 days | Drug: H. pylori eradication scheme E<br>* Esomeprazole 40mg bid + amoxicillin 1g 12/12h for 7 days, followed by esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 12/12h for 7 days<br>* Other names: Hybrid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy assessed by the eradication rate of the different therapeutic regimens recommended as H. pylori eradication therapy | Efficacy rate of H. pylori eradication will be determined for five different therapeutic regimens (sequential, hybrid and concomitants with or without bismuth). A successful eradication implies no documentation of H. pylori by carbon 13-labeled urea breath test or upper gastrointestinal endoscopy with biopsies, depending on clinical indication, at 1 month after H. pylori eradication (D40 or D44). A therapeutic regimen will be considered effective if it achieves more than 90% of H. pylori eradication (the minimum efficacy rate). | 1 month after the intervention | 
| Efficacy assessed by the re-infection rate after the different therapeutic regimens recommended as H. pylori eradication therapy | At 12 months after H. pylori eradication, a carbon 13-labeled urea breath test will be performed to exclude re-infection. | 12 months after the intervention | 
| Safety assessed by overall treatment-adverse events and and severe treatment-adverse events rates of the different therapeutic regimens recommended as H. pylori eradication therapy | Safety profile of H. pylori eradication will be determined for five different therapeutic regimens measuring adverse effects according to Medical Dictionary for Regulatory Activities (MedDRa). Therapy-related adverse events and its severity (by visual analogue scale of intolerance [0-10] and classification of the severity of adverse effects for the daily life activities according to [BoThBo96]) will be recorded at 1 month post-eradication follow-up. | 1 month after the intervention | 
| Safety assessed by overall treatment completion rate of the different therapeutic regimens recommended as H. pylori eradication therapy | Safety profile of H. pylori eradication will be determined for five different therapeutic regimens measuring the treatment completion rate to the treatment at 1 month post-eradication follow-up. | 1 month after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-eradication changes assessed by OTU and their relative abundance in gut microbiota | Stool samples shall be collected, stored at -20°C and then analyzed on 3 occasions: 1) baseline, 2) after stopping treatment (D10 or 14) and 3) 1 month after treatment (D40 or 44). A standard protocol with the conditions of collection, storage and transport of the different collected samples will be used. Analysis of gut microbiota by DNA sequencing using the hypervariable region of the 16S ribosomal bacteria gene as a taxonomic identification marker by bioinformatic analysis, for taxonomic identification and determination of the relative abundance of each Operational Taxonomy Units (OTU). The gut microbiota will be evaluated by an independent operator who does not know the therapeutic scheme used. | Changes from baseline at immediately after the intervention | 
| Post-eradication changes assessed by OTU and their relative abundance in gut microbiota | Stool samples shall be collected, stored at -20°C and then analyzed on 3 occasions: 1) baseline, 2) after stopping treatment (D10 or 14) and 3) 1 month after treatment (D40 or 44). A standard protocol with the conditions of collection, storage and transport of the different collected samples will be used. Analysis of gut microbiota by DNA sequencing using the hypervariable region of the 16S ribosomal bacteria gene as a taxonomic identification marker by bioinformatic analysis, for taxonomic identification and determination of the relative abundance of each Operational Taxonomy Units (OTU). The gut microbiota will be evaluated by an independent operator who does not know the therapeutic scheme used. | Changes from baseline at 1 month after the intervention |