Tailored vs. Empirical Helicobacter Pylori Infection Treatment

Susceptibility-guided vs. Empirical First-line Bismuth Quadruple Therapy of H. Pylori Infection: a National Prospective Multicentric Randomized Controlled Trial.

Helicobacter pylori (Hp) is a gram-negative bacterium that colonizes human gastric mucosa and is associated with chronic gastritis that can progress to severe complications such as peptic ulcer disease, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma. More than half of the world's population is infected with H. pylori and Portugal is one of the countries with the highest Hp burden. All of infected patients should be treated, however, H. pylori treatment is challenged by the continuously rising antibiotic resistance which has reached alarming levels worldwide. For this reason, it is now well accepted that tailoring treatment of H. pylori infection based on systematic antimicrobial susceptibility testing is useful to avoid the increase of antibiotic resistance.

Our aims are to determine prospectively the efficacy and safety of first-line H. pylori eradication treatment based on resistance profile (determined by molecular methods) vs. empirical bismuth quadruple therapy, to evaluate the accuracy of H. pylori detection by polymerase chain reaction (PCR) (vs. histopathological examination) and to estimate the prevalence of H. pylori infection and H. pylori resistance to clarithromycin and levofloxacin in Portugal.

This prospective study will be the first national study to investigate the benefits of tailored H. pylori eradication treatment. The investigators expect that this project will be able to demonstrate the non-inferiority of susceptibility-guided treatment comparing with empirical therapy, and our results may change H. pylori treatment recommendations by systematically applying antibiotic susceptibility testing before prescribing eradication therapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Helicobacter Pylori Infection
• Intervention / Treatment: Diagnostic test: Clarithromycin (mutations in the 23S rRNA gene, A2134G, A2142G and A2142C mutations) and levofloxacin resistance (mutations in the gyrA gene) PCR test; Drug: PPI, amoxicillin 1 g and clarithromycin 500 mg, twice daily, for 10 days; Drug: PPI, amoxicillin 1g and levofloxacin 250 mg, twice daily, for 10 days; Drug: Bismuth quadruple therapy (Pylera®) for 10 days; Drug: Empirically H. pylori eradication treatment with bismuth quadruple therapy (Pylera®)

Detailed Description

A prospective, multicenter, randomized, controlled interventional trial in two arms: intervention group and control group.

Eligible patients will receive oral and written information and will be enrolled after giving written informed consent.

In all patients complete gastroscopy with white light will be performed and endoscopic findings will be recorded. For each patient, gastric body and antral biopsies will be collected. All gastric samples will be tested for H. pylori infection by histopathological examination and PCR. All H. pylori positive samples will be tested for clarithromycin (mutations in the 23S rRNA gene, A2134G, A2142G and A2142C mutations) and levofloxacin resistance (mutations in the gyrA gene) by PCR.

All H. pylori positive patients will be randomized in two groups:

INTERVENTION GROUP: Patients randomized to the Intervention group will receive a prescription for oriented H. pylori eradication treatment according to the following rules: a) clarithromycin-sensitive strain (independently of levofloxacin resistance test result) - PPI, amoxicillin 1 g and clarithromycin 500 mg, twice daily, for 10 days; b) clarithromycin-resistant and levofloxacin-sensitive strain - PPI, amoxicillin 1g and levofloxacin 250 mg, twice daily, for 10 days; c) clarithromycin-resistant and levofloxacin-resistant strain - bismuth quadruple therapy (Pylera®) for 10 days. At least 4 weeks after stopping antibiotics (and at least 2 weeks after stopping PPIs), an eradication control test will be carried out using a respiratory test (urea breath test) or endoscopic biopsies (if clinical indication for that).

CONTROL GROUP: Patients randomized to the Control group will receive a prescription for empirically H. pylori eradication treatment with bismuth quadruple therapy (Pylera®) for 10 days. At least 4 weeks after stopping antibiotics (and at least 2 weeks after stopping PPIs), an eradication control test will be carried out using a respiratory test (urea breath test) or endoscopic biopsies (if clinical indication for that).

All patients that complete eradication treatment regimen will be evaluated 2 to 4 weeks after performing the eradication control (urea breath test) in a clinical consultation. Eventual adverse effects will be recorded. A negative breath test will define the success of the treatment, while a positive test will define treatment failure. The latter will be managed according to H. pylori infection guidelines.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 4

Contacts and Locations

Study Locations

• Portugal
  • Porto, Portugal, 4150-178
    • Unilabs Portugal
    • Contact: Manuel Coelho da Rocha, MD; Phone Number: +351964607421; Email: manuel.rocha@external.unilabs.com
    • Contact: Pedro Pimentel Nunes, MD PhD; Phone Number: +351967340096; Email: pedro.nunes@external.unilabs.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Individuals older than 18 years old scheduled for upper GI endoscopy with indication for gastric biopsies (clinical or endoscopic findings)

Exclusion Criteria:

• 1st phase (clinical): patients who had received antimicrobial therapy 1 month prior to endoscopy; patients who had received proton pump inhibitor (PPI) therapy 2 weeks prior to endoscopy; patients who had ever received H. pylori eradication therapy (despite its efficacy); history of previous gastrectomy; non-Portuguese nationality; pregnant or breastfeeding women; women of childbearing age without effective contraception; suspected or documented allergy to amoxicillin; serious comorbidities (ASA 3 or more); ongoing medication with anticoagulants
• 2nd phase (endoscopic): upper GI tract neoplasia; hemorrhagic gastritis; upper GI tract varices
• 3rd phase (pathological): H. pylori negative patients

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention group; Patients randomized to the Intervention group will receive a prescription for oriented H. pylori eradication treatment according to the following rules: a) clarithromycin-sensitive strain (independently of levofloxacin resistance test result) - PPI, amoxicillin 1 g and clarithromycin 500 mg, twice daily, for 10 days; b) clarithromycin-resistant and levofloxacin-sensitive strain - PPI, amoxicillin 1g and levofloxacin 250 mg, twice daily, for 10 days; c) clarithromycin-resistant and levofloxacin-resistant strain - bismuth quadruple therapy (Pylera®) for 10 days. At least 4 weeks after stopping antibiotics (and at least 2 weeks after stopping PPIs), an eradication control test will be carried out using a respiratory test (urea breath test) or endoscopic biopsies (if clinical indication for that).	Diagnostic test: Clarithromycin (mutations in the 23S rRNA gene, A2134G, A2142G and A2142C mutations) and levofloxacin resistance (mutations in the gyrA gene) PCR test; Described in "Arms" section; Drug: PPI, amoxicillin 1 g and clarithromycin 500 mg, twice daily, for 10 days; Administered to patients randomized to Intervention group and with H. pylori clarithromycin-sensitive strain; Drug: PPI, amoxicillin 1g and levofloxacin 250 mg, twice daily, for 10 days; Administered to patients randomized to Intervention group and with H. pylori clarithromycin-resistant and levofloxacin-sensitive strain; Drug: Bismuth quadruple therapy (Pylera®) for 10 days; Administered to patients randomized to Intervention group and with H. pylori clarithromycin-resistant and levofloxacin-resistant strain
Active Comparator: Control group; Patients randomized to the Control group will receive a prescription for empirically H. pylori eradication treatment with bismuth quadruple therapy (Pylera®) for 10 days. At least 4 weeks after stopping antibiotics (and at least 2 weeks after stopping PPIs), an eradication control test will be carried out using a respiratory test (urea breath test) or endoscopic biopsies (if clinical indication for that).	Drug: Empirically H. pylori eradication treatment with bismuth quadruple therapy (Pylera®); Described in "Arms" section

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of successful H. pylori eradication treatment in intervention group vs. control group.	This comparation will allow the investigators to show the non-inferiority of susceptibility-guided treatment comparing with empirical therapy	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of H. pylori detection in gastric samples by PCR vs. histopathological examination.	All gastric samples will be tested for H. pylori infection by histopathological examination and PCR. This comparation will allow the investigators to analyze tha diagnostica accuracy of PCR vs. histopathological examination	12 months
Estimate the prevalence of H. pylori infection in Portugal.		12 months
Estimate the prevalence of H. pylori resistance to clarithromycin and levofloxacin in Portugal.		12 months

Collaborators and Investigators

• Sponsor: Manuel Coelho da Rocha

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2024
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: December 12, 2023
• First Submitted That Met QC Criteria: December 30, 2023
• First Posted (Estimated): January 11, 2024

Study Record Updates

• Last Update Posted (Estimated): January 11, 2024
• Last Update Submitted That Met QC Criteria: December 30, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Helicobacter pylori; Eradication treatment; Antibiotic resistance; Molecular pathology
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Communicable Diseases; Helicobacter Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Gastrointestinal Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Anti-Ulcer Agents; Cytochrome P-450 CYP1A2 Inhibitors; Antacids; Anti-Infective Agents, Urinary; Metronidazole; Amoxicillin; Clarithromycin; Levofloxacin; Ofloxacin; Bismuth; Tetracycline; Bismuth tripotassium dicitrate
• Other Study ID Numbers: Clinical Study Protocol 1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: Starting in May 2025
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No