Helicobacter Pylori Eradication Therapy in Portugal

July 3, 2022 updated by: Elisa Gravito-Soares, Centro Hospitalar e Universitário de Coimbra, E.P.E.

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

230

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Elisa Gravito-Soares, MD
  • Phone Number: (+351)239400483
  • Email: es18497@gmail.com

Study Contact Backup

Study Locations

  • Portugal
      • Coimbra, Portugal, 3000-075
        • Recruiting
        • Centro Hospitalar e Universitário de Coimbra
        • Contact:
        • Contact:
        • Principal Investigator:
          • Elisa Gravito-Soares, MD
        • Principal Investigator:
          • Nuno Almeida, PhD
        • Sub-Investigator:
          • Marta Gravito-Soares, MD
        • Sub-Investigator:
          • Bárbara Rocha, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: H. pylori eradication scheme A
Esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 8/8h, for 14 days
Drug: H. pylori eradication scheme A
Esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 8/8h, for 14 days
Other Names:
  • Concomitant bismuth-free A
Experimental: H. pylori eradication scheme B
Esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 12/12h, for 14 days
Drug: H. pylori eradication scheme B
Esomeprazole 40mg bid + amoxicillin 1g 12/12h + clarithromycin 500mg 12/12h + metronidazole 500mg 12/12h, for 14 days
Other Names:
  • Concomitant bismuth-free B
Experimental: H. pylori eradication scheme C
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
Esomeprazole 40mg bid + bismuth subsalicylate 420mg 6/6h + metronidazole 375mg 6/6h + tetracycline 375mg 6/6h, for 10 days
Other Names:
  • Pylera
  • Concomitant with bismuth
Experimental: H. pylori eradication scheme D
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
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
Other Names:
  • Sequential
Experimental: H. pylori eradication scheme E
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
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
Other Names:
  • Hybrid

What is the study measuring?

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
Time Frame: 1 month after the intervention
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
Time Frame: 12 months after the intervention
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
Time Frame: 1 month after the intervention
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
Time Frame: 1 month after the intervention
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
Time Frame: Changes from baseline at immediately after the intervention
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
Time Frame: Changes from baseline at 1 month after the intervention
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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Post-eradication changes assessed by immunological cells populations in immunological profile
Time Frame: Changes from baseline at 12 months after the intervention
Fresh peripheral blood samples will be collected and analyzed on 2 occasions: 1) baseline and 2) 12 months after treatment. A standard protocol with the conditions of collection, storage and transport of the different collected samples will be used. Analysis of immunological changes: Immunological profile will be analysed through the study of cell populations (CD4+, CD8+, B-cell, T-cell, natural killer cells, cells ratio) by multiparametric flow cytometry, before and 12 months after the H. pylori eradication therapy, by an independent operator who does not know the therapeutic scheme used.
Changes from baseline at 12 months after the intervention
Post-eradication changes assessed by cytokines, chemokines and growth factors in immunological profile
Time Frame: Changes from baseline at 12 months after the intervention
Fresh peripheral blood samples will be collected and analyzed on 2 occasions: 1) baseline and 2) 12 months after treatment. A standard protocol with the conditions of collection, storage and transport of the different collected samples will be used. Analysis of immunological changes: Immunological profile will be analysed through the study of cytokines, chemokines and growth factors by xMAP/Luminex, before and 12 months after the H. pylori eradication therapy, by an independent operator who does not know the therapeutic scheme used.
Changes from baseline at 12 months after the intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centro Hospitalar e Universitário de Coimbra, E.P.E.

Collaborators

University of Coimbra

Investigators

  • Principal Investigator: Elisa Gravito-Soares, MD, Centro Hospitalar e Universitário de Coimbra, E.P.E.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2022

Primary Completion (Anticipated)

December 31, 2023

Study Completion (Anticipated)

December 31, 2024

Study Registration Dates

First Submitted

May 22, 2022

First Submitted That Met QC Criteria

July 3, 2022

First Posted (Actual)

July 8, 2022

Study Record Updates

Last Update Posted (Actual)

July 8, 2022

Last Update Submitted That Met QC Criteria

July 3, 2022

Last Verified

July 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HpETIP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

No applicable.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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