The primary objective of this study is to compare the Helicobacter pylori (H. pylori) eradication rate following empiric bismuth-based quadruple therapy (BQT) versus a personalized H. pylori treatment strategy in treatment-naïve Veterans with confirmed H. pylori infection.
This study is an eight-week, parallel two-arm, double-blinded, prospective, single-site randomized clinical trial designed to test the hypothesis that personalized H. pylori therapy achieves higher eradication rates compared to the standard empiric BQT regimen. Secondary outcomes include comparisons of treatment adherence, tolerability, and the incidence of treatment-related side effects and adverse events between the two groups. A total of 360 treatment-naïve Veterans with active H. pylori infection, confirmed by a positive H. pylori stool antigen test (HPsAg), will be enrolled, randomized, and analyzed at the VA San Diego Healthcare System (VASDHS). Participants who meet eligibility criteria and provide informed consent will be randomized in a 1:1 ratio to receive either a 14-day personalized H. pylori treatment regimen (n=180) or a standard 14-day empiric BQT regimen (n=180).
Participants randomized to personalized therapy will receive H. pylori treatment that incorporates 1) standard or optimized proton pump inhibitor (PPI) dosing according to participants' CYP2C19 metabolizer phenotype, and 2) tailored antibiotics according to participants' noninvasive (stool) H. pylori antibiotic susceptibility testing (AST). All participants will complete a baseline questionnaire and provide pre-treatment stool and blood samples for H. pylori AST and serum CYP2C19 testing, respectively. Follow-up will include brief telephone interviews during week 1 and week 2 of treatment and again two weeks post-treatment to assess adherence and monitor for adverse events. Cure will be assessed using a post-treatment stool antigen test (HPsAg) at week 8 (four weeks after completing therapy).
Adult Veterans, irrespective of sex/gender (male, female, non-binary, other preferred classification)
Treatment-naïve patients with active H. pylori infection as determined by a positive H. pylori stool antigen (HPsAg), gastric biopsy, or urease breath test. All individuals who test positive based on a non-HPsAg modality will need to have a positive HPsAg documented within 4 weeks of enrollment to be considered eligible
Subjects who can understand and sign written informed consent
Severe gastrointestinal (GI) symptoms that limit the ability to tolerate study medications. Note: The presence of symptoms or gastrointestinal diagnoses such as irritable bowel syndrome or gastroesophageal reflux does not impact H. pylori eradication and will not be exclusion criteria unless deemed that symptom severity will impact adherence.
Conditions where urgent H. pylori treatment is recommended (i.e., active peptic ulcer disease (PUD) complicated by bleeding, perforation, or obstruction; gastric neoplasia including MALT lymphoma). Active PUD is defined as having a gastric or duodenal ulcer confirmed on an upper endoscopic procedure in the 4 weeks prior to eligibility determination
Inability to be safely off of PPI for two weeks to allow for accurate post-treatment HPsAg testing. These conditions include Barrett's esophagus with dysplasia, active PUD, severe esophagitis defined as Los Angeles Classification C or D esophagitis
Allergy or severe intolerance/contraindication to any of the treatment components. Note: In patients with penicillin allergy, metronidazole is often substituted for amoxicillin in PPI clarithromycin triple therapy. However, this alternative regimen demonstrates higher failure rates vs. PPI-clarithromycin triple therapy with amoxicillin among Veterans and thus the investigators elected to exclude patients with penicillin allergy.
Parallel
Bismuth quadruple therapy with optimized proton pump inhibitor (PPI)
DrugBismuth 524 milligrams QID, Metronidazole 500 milligrams QID, Tetracycline 500 milligrams QID, and Omeprazole 20 milligrams QID for 14 days.
Bismuth quadruple therapy with standard proton pump inhibitor (PPI)
DrugBismuth 524 milligrams QID, Metronidazole 500 milligrams QID, Tetracycline 500 milligrams QID, and Omeprazole 20 milligrams (active BID + placebo BID) for 14 days. \*\*NOTE: placebo tablets are used to maintain the same number of pills in all study arms and preserve blinding
Clarithromycin triple therapy with optimized proton pump inhibitor (PPI)
DrugAmoxicillin 1000 milligrams (active BID + placebo BID), Clarithromycin 500 milligrams (active BID + placebo BID), and Omeprazole 20 milligrams QID for 14 days. \*\*NOTE: placebo tablets are used to maintain the same number of pills in all study arms and preserve blinding
Clarithromycin triple therapy with standard PPI
DrugAmoxicillin 1000 milligrams (active BID + placebo BID), Clarithromycin 500 milligrams (active BID + placebo BID), and Omeprazole 20 milligrams (active BID + placebo BID) for 14 days. \*\*NOTE: placebo tablets are used to maintain the same number of pills in all study arms and preserve blinding
Standard bismuth quadruple therapy
DrugBismuth 524 milligrams QID, Metronidazole 500 milligrams QID, Tetracycline 500 milligrams QID, and Omeprazole 20 milligrams (active BID + placebo BID) for 14 days. \*\*NOTE: placebo tablets are used to maintain the same number of pills in all study arms and preserve blinding
H. pylori eradication success
The primary outcome is H. pylori eradication success, defined as negative post-treatment H. pylori stool antigen (HPsAg) testing. Post-treatment persistent positive HPsAg indicates eradication treatment failure; equivocal tests will be conservatively counted as a treatment failure, along with participants who fail to complete follow up testing within the prespecified timeframe (intention-to-treat analysis). All participants must be off proton pump inhibitors (PPIs) for a minimum of 2 weeks, and off antibiotics or bismuth for at least 4 weeks prior to HPsAg testing. HPsAg testing will be performed between 4-6 weeks post-treatment.
Treatment adherence
Patient-reported treatment adherence will be evaluated using the validated Adherence to Refills and Medications Scale (ARMS) and pill counts obtained during telephone interviews conducted in weeks 1 and 2 following treatment initiation. Adherence will be defined as \>90% of the treatment regimen consumed.
Treatment-emergent side effects/adverse events
Participant-reported side effects and adverse events will be collected during telephone interviews conducted in weeks 1 and 2 following treatment initiation, and in week 6 following treatment completion. Treatment-emergent adverse events will be classified using the Medical Dictionary for Regulatory Activities terminology (MedDRA).
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VA Office of Research and Development
Lead sponsor
San Diego Veterans Healthcare System
Collaborator
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