Genotypic Resistance Guided Therapy for Refractory H. Pylori Infection

Comparison of Genotypic Resistance Guided Versus Susceptibility Testing Guided Therapy for the Third-line Eradication of H. Pylori- a Multicenter Randomized Trial

The inviestigators aimed to compare the efficacy of genotypic resistance guided versus susceptibility testing guided therapy in the third line treatment for refractory H. pylori infection.

Hypothesis:The investigators hypothesized that genotypic resistance guided sequential therapy is non-inferior to empiric therapy in the third line treatment for refractory H. pylori infection.

Methods: This multicenter, open label, parallel group, randomized trial will be conducted since 2017.07.20. Adult (≥20 years old) patients who failed from at least two eradication therapies for H. pylori infection will be enrolled. Genotypic and phenotypic resistances will be determined in patients who failed from at least two eradication therapies by polymerase-chain-reaction with direct sequencing and E-test and agar dilution test, respectively. Eligible patients will be randomized into either one of the treatment groups (A) genotypic resistance guided therapy; or (B) susceptibility testing guided therapy.

Outcome Measurement The primary outcome is the eradication rate in the third line treatment (genotypic versus susceptibility testing guided therapy) according to intention-to-treat (ITT) analysis.

Study Overview

• Status: Unknown
• Conditions: H Pylori Infection
• Intervention / Treatment: Drug: Esomeprazole 40mg; Drug: Amoxicillin; Drug: metronidazole; Drug: Levofloxacin 500mg; Drug: Clarithromycin ER; Drug: Esomeprazole 40mg; Drug: Dibismuth trioxide; Drug: metronidazole; Drug: tetracycline

Detailed Description

The inviestigators aimed to compare the efficacy of genotypic resistance guided versus susceptibility testing guided therapy in the third line treatment for refractory H. pylori infection.

Hypothesis:The investigators hypothesized that genotypic resistance guided sequential therapy is non-inferior to empiric therapy in the third line treatment for refractory H. pylori infection.

Methods: This multicenter, open label, parallel group, randomized trial will be conducted since 2017.07.20. Adult (≥20 years old) patients who failed from at least two eradication therapies for H. pylori infection will be enrolled. Genotypic and phenotypic resistances will be determined in patients who failed from at least two eradication therapies by polymerase-chain-reaction with direct sequencing and E-test and agar dilution test, respectively. Eligible patients will be randomized into either one of the treatment groups (A) genotypic resistance guided therapy; or (B) susceptibility testing guided therapy. Eradication status will be determined by 13C-urea breath test at least 6 weeks after eradication therapy. The stool samples will be collected before, and 2 and 8 weeks and 1 year after eradication therapy to analyze the changes in the antibiotic resistance and microbiota of gut flora. The body weight, waist and hip circumference and serum lipid profile, sugar, and HbA1C levels will also be collected before and 2 weeks, 8 weeks and 1 year after eradication therapy.

Outcome Measurement The primary outcome is the eradication rate in the third line treatment (genotypic versus susceptibility testing guided therapy) according to intention-to-treat (ITT) analysis.

Secondary End Points: the eradication rate according per protocol analysis and the adverse effects

Secondary End Point:

(A) Eradication rate according to per protocol analysis (PP analysis) (B) Frequency of adverse effects (C) The changes in the gut microbiota, antibiotic resistance of the Enterobacteriae, metabolic parameters before and after H. pylori eradication (D) The long term eradication rate and reinfection rate

• Study Type: Interventional
• Enrollment (Anticipated): 320
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jyh-Ming Liou, MD, PhD; Phone Number: 886972651883; Email: jyhmingliou@gmail.com
• Study Contact Backup: Name: Mei-Jyh Chen, MD; Phone Number: 63541 886223123456; Email: migichen@ntuh.gov.tw

Study Locations

• Taiwan
  • Taiwan-
    • Taipei, Taiwan, Taiwan-, Taiwan, 10002
      • Recruiting
      • Jyh-Ming Liou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• H pylori infection failed after at least two eradication therapies
• aged 20 years or greater
• willingness to receive rescue therapy

Exclusion Criteria:

• aged less than 20 years
• history of gastric resection surgery
• history of allergy to study drugs
• pregnancy or lactating women
• severe underlying illness, such as end stage renal disease, decompensated liver cirrhosis, or non-curative malignancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Genotypic resistance guided therapy; The regimen will be chosen according to the genotyping of 23S rRNA and gyrase A of H. pylori. In the absence of gyrase A mutation, esomeprazole (Nexium), amoxicillin (Amoxicillin), levofloxacin (Cravit), metronidazole (Flagyl) for 14 days will be given. In the presence of gyrase A mutation but in the absence of 23S rRNA mutation, esomeprazole (Nexium), amoxicillin (Amoxicillin), clarithromycin (Klaricid), metronidazole (Flagyl) for 14 days will be given. In the presence of both gyrase A and 23S rRNA mutation, bismuth quadruple therapy including esomeprazole (Nexium), bismuth (KCB), tetracycline, and metronidazole (Flagyl) for 10 days will be given.	Drug: Esomeprazole 40mg; Nexium (esomeprazole), 40mg, bid, for 14 days; Other Names: Nexium (Sequential); Drug: Amoxicillin; amoxicillin, 1000mg, bid, for 7 days (day 1-day 7); Other Names: Amoxicillin (Sequential); Drug: metronidazole; metronidazole, 500mg, bid, for 7 days (day 8-14); Other Names: Flagyl (sequential); Drug: Levofloxacin 500mg; levofloxacin 250mg, bid, for 7 days (day 8-14); Other Names: Cravit (sequential); Drug: Clarithromycin ER; clarithromycin 500mg, bid, for 7 days (day 8-14); Other Names: Klaricid ER 500 (sequential); Drug: Esomeprazole 40mg; Nexium (esomeprazole), 40mg, bid, for 10 days; Other Names: Nexium (bismuth quadruple therapy); Drug: Dibismuth trioxide; Dibismuth trioxide，KCB F.C. TABLETS，300mg，qid, for 10 days; Other Names: KCB F.C.; bismuth; Drug: metronidazole; metronidazole, 500mg, tid, for 10 days (day 1-10); Other Names: Flagyl (bismuth quadruple); Drug: tetracycline; tetracycline 500mg, qid, for 10 days; Other Names: tetracycline (bismuth quadruple therapy)
Active Comparator: Phenotypic resistance guided therapy; The regimen will be chosen according to the susceptibility testing result. In the absence of levofloxacin resistance, esomeprazole (Nexium), amoxicillin (Amoxicillin), levofloxacin (Cravit), metronidazole (Flagyl) for 14 days will be given. In the presence of levofloxacin resistance but in the absence of clarithromycin resistance, esomeprazole (Nexium), amoxicillin (Amoxicillin), clarithromycin (Klaricid), metronidazole (Flagyl) for 14 days will be given. In the presence of both levofloxacin and clarithromycin resistance, bismuth quadruple therapy including esomeprazole (Nexium), bismuth (KCB), tetracycline, and metronidazole (Flagyl) for 10 days will be given.	Drug: Esomeprazole 40mg; Nexium (esomeprazole), 40mg, bid, for 14 days; Other Names: Nexium (Sequential); Drug: Amoxicillin; amoxicillin, 1000mg, bid, for 7 days (day 1-day 7); Other Names: Amoxicillin (Sequential); Drug: metronidazole; metronidazole, 500mg, bid, for 7 days (day 8-14); Other Names: Flagyl (sequential); Drug: Levofloxacin 500mg; levofloxacin 250mg, bid, for 7 days (day 8-14); Other Names: Cravit (sequential); Drug: Clarithromycin ER; clarithromycin 500mg, bid, for 7 days (day 8-14); Other Names: Klaricid ER 500 (sequential); Drug: Esomeprazole 40mg; Nexium (esomeprazole), 40mg, bid, for 10 days; Other Names: Nexium (bismuth quadruple therapy); Drug: Dibismuth trioxide; Dibismuth trioxide，KCB F.C. TABLETS，300mg，qid, for 10 days; Other Names: KCB F.C.; bismuth; Drug: metronidazole; metronidazole, 500mg, tid, for 10 days (day 1-10); Other Names: Flagyl (bismuth quadruple); Drug: tetracycline; tetracycline 500mg, qid, for 10 days; Other Names: tetracycline (bismuth quadruple therapy)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Eradication rate by intention to treat analysis	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Eradication rate by per protocol analysis		8 weeks
frequency of adverse effects during eradication therapy		2 weeks
changes of fecal microbiota	changes of fecal microbiota before and after erdication therapy	1 year
reinfection rate	reinfection rate 1 year after eradication therapy	1 year

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Jyh-Ming Liou, MD, PhD, National Taiwan University Hospital (recruiting); Principal Investigator: Yen-Nien Chen, MD, National Taiwan University Hospital Hsin-Chu Branch; Principal Investigator: Yu Jen Fang, MD, National Taiwan University Hospital, Yun-Lin Branch

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2017
• Primary Completion (Anticipated): September 1, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: December 14, 2017
• First Submitted That Met QC Criteria: June 12, 2018
• First Posted (Actual): June 13, 2018

Study Record Updates

• Last Update Posted (Actual): June 13, 2018
• Last Update Submitted That Met QC Criteria: June 12, 2018
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: 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; Proton Pump Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Antacids; Anti-Infective Agents, Urinary; Renal Agents; Metronidazole; Amoxicillin; Clarithromycin; Levofloxacin; Ofloxacin; Esomeprazole; Bismuth; Tetracycline
• Other Study ID Numbers: 201706037MINC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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