Clinical trial NCT02547038
Conditions: Helicobacter Pylori Infection
Keywords: Helicobacter pylori Eradication rate
Sponsor: Kaohsiung Veterans General Hospital.
Start date: 2015-02-01; Completion date: 2018-10-01
Enrollment: 352 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Reverse hybrid therapy achieves a higher eradication rate than bismuth quadruple therapy remained unanswered.

Detailed description:
A 14-day hybrid therapy invented by our study group appears very promising in H. pylori eradication, achieving excellent eradication rates of 99% and 97% according to per-protocol and intention-to-treat analyses, respectively. Recently, the investigators demonstrated that the eradication rate of reverse hybrid therapy was higher than that of standard triple therapy. However, whether reverse hybrid therapy achieves a higher eradication rate than bismuth quadruple therapy remained unanswered.

Arms: arm 1: pantoprazole 40 mg twice daily, bismuth subcitrate 120 mg four times daily, and tetracycline 500 mg four times daily, and metronidazole 250 mg four times daily for 14 days arm 2: a 7-day quadruple regimen with pantoprazole 40 mg twice daily, amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice daily, followed by a 7-day dual regimen with pantoprazole 40 mg twice daily and amoxicillin 1 g twice daily
Interventions: intervention 1: pantoprazole+bismuth+tetra+metro intervention 2: (panto+amox+clar+metr)+(panto+amox)
Intervention descriptions: intervention 1: pantoprazole 40 mg twice daily, bismuth subcitrate 120 mg four times daily, and tetracycline 500 mg four times daily, and metronidazole 250 mg four times daily for 14 days intervention 2: a 7-day quadruple regimen with pantoprazole 40 mg twice daily, amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice daily, followed by a 7-day dual regimen with pantoprazole 40 mg twice daily and amoxicillin 1 g twice daily

Protocol documents:
Prot_SAP_000.pdf: 
VGHKS15-CT2-10
Institution/Department：Kaohsiung Veterans General Hospital
Principal Investigator (PI)：Prof. Ping-I Hsu 
Research Project  Title ：Comparing the efficacy and impact on gastrointestinal 
microbiome  of reverse  hybrid  therapy  and  bismuth 
quadruple therapy in Helicobacter pylori eradication
NCT Number：NCT02547038
Date of the document：  01 
    02   2019  （MM/DD/YYYY） 
ABSTRACT
Background: With the rising prevalence of antimicrobial resistance, the failure rate of the 
standard triple therapy has declined to unacceptable level (<80%) worldwide. A 14-day hybrid 
therapy invented by our study group appears very promising in H. pylori eradication, achieving 
excellent eradication rates of 99% and 97% according to per-protocol and intention-to-treat 
analyses, respectively. Recently, we demonstrated  that  the eradication rate of reverse hybrid 
therapy was higher than that of standard triple therapy. However, whether reverse hybrid therapy 
achieves a higher eradication rate than bismuth quadruple therapy remained unanswered. 
Aims: The aims of this randomized controlled trial are (1) to compare the efficacies of reverse 
hybrid therapy and bismuth quadruple therapy, (2) to investigate the host and bacterial factors 
predicting the treatment outcomes of the two eradication regimens. 
Methods: Consecutive 352 H. pylori-infected subjects are randomly assigned to receive either a 
14-day reverse hybrid therapy or a 14-day bismuth quadruple therapy. On recruitment, blood 
sampling for genotyping of  CYP2C19 is carried out, and antibiotic susceptibility of  H pylori 
strains will be checked. Subjects are asked to return at the end of the 2nd week to assess drug 
compliance and adverse events. H pylori status will be re-assessed at week 6 after the end of anti- 
H. pylori therapy. Finally, the rates  of eradication, adverse events and compliance will be 
compared between groups by chi-square test, and the host and bacterial factors influencing each 
efficacy of the regimen are assessed by multivariate analysis.
Introduction
Helicobacter pylori (H. pylori) infection is the principal cause of chronic gastritis, gastric ulcer, 
duodenal ulcer, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma.1 
In most international guidelines,2-4 14-day standard triple therapy is still recommended as a choice 
of  treatment  for  the  first-line  therapy  of  H.  pylori infection,  especially  in  areas  of  low 
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clarithromycin resistance (< 15%). However, the eradication rates of standard triple therapy have 
declined  to less than 80% in most countries because of the rising prevalence of clarithromycin 
resistance.5 Several strategies including  bismuth-containing quadruple therapy and non-bismuth- 
containing quadruple therapy have therefore been proposed to increase the eradication rate.5,6
   In the Maastricht V/Florence Consensus Report,3 bismuth quadruple therapy is the treatment of 
choice for the first-line therapy of H. pylori infection in areas of high clarithromycin resistance (> 
15%) and an alternative in areas of low clarithromycin resistance. In the recent American College of 
Gastroenterology (ACG) guideline, it is also recommended as a first-line treatment for H. pylori 
infection.4 However, the complicated administration of bismuth quadruple therapy easily reduces 
the adherence of patients, and the complex therapy is associated with a high frequency of adverse 
events.7,8
   Hybrid therapy developed by Hsu et al. in 2011 consists of a dual therapy with a proton pump 
inhibitor (PPI) and amoxicillin for 7 days followed by a quadruple regimen with a PPI, amoxicillin, 
clarithromycin and metronidazole for 7 days.6 It achieved an eradication rate of 97.4% by intention-
to-treat (ITT) analysis and 99.1% by per-protocol (PP) analysis in Taiwan.6 Subsequent randomized 
controlled trials demonstrated that 14-day hybrid therapies were comparable or more effective than 
10-day sequential therapies.9,10 A recent large multicentre randomized controlled trial documented 
that 14-day hybrid and 14-day concomitant therapies had comparable efficacy in the treatment of H. 
pylori infection, and both could cure more than 90% of patients with H. pylori infections in areas of 
high  clarithromycin  and  metronidazole  resistance.11 Currently,  it  is  a  recommended  first-line 
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treatment choice in the ACG guideline4 and the Taiwan Helicobacter pylori Consensus Report.12
However, hybrid therapy requires additional two antibiotics in the last 7 days, which can 
confuse  patients  and  may  dampen  enthusiasm  for  its  use.  Reversing  the  sequence  of  drug 
administration (a quadruple regimen followed by a dual regimen) can simplify hybrid therapy. The 
aims of this randomized controlled trial are (1) to compare the efficacies of reverse hybrid therapy 
and bismuth quadruple therapy, (2) to investigate the host and bacterial factors predicting the 
treatment outcomes of the two eradication regimens. 
PATIENTS & METHODS
Study population
   The open-labeled trial is conducted at the Kaohsiung Veterans General Hospital and Kaohsiung 
Medical University Hospital in Taiwan in accordance with the principles of good clinical practice 
from the Declaration of Helsinki. The study protocol will be approved by the Ethics Committees 
of the Kaohsiung Veterans General Hospital and the Kaohsiung Medical University Hospital. All 
patients give written informed consent before participating in the study.
   We will recruit  352 patients to the study if they meet the following criteria: they are adult 
patients aged  20 years and have H pylori infection. The exclusion criteria include The exclusion 
criteria include (1) previous H pylori-eradication therapy, (2) patient with allergic history to the 
medications  used,   (3)  patients  with  previous  gastric  surgery,  (4)  coexistence  of  serious 
concomitant  illness  (for  example,  decompensated  liver  cirrhosis,  uremia),  and  (5)  pregnant 
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women.
Randomization and treatment
This  is  a  randomized  controlled  trial.  Eligible  H.  pylori-infected  subjects  are  randomly 
assigned to a 14-day reverse hybrid therapy (a 7-day quadruple regimen with pantoprazole 40 mg 
twice daily, amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 
mg twice daily, followed by a 7-day dual regimen with pantoprazole 40 mg twice daily and 
amoxicillin 1 g twice daily) or a 14-day bismuth quadruple therapy (pantoprazole 40 mg twice 
daily, bismuth tripotassium dicitrate 120 mg, and tetracycline 500 mg four times daily for 14 days). 
All drugs are taken one hour before breakfast and dinner. Patients with peptic ulcers in initial 
endoscopy receive an additional 4-week pantoprazole therapy (40 mg orally once daily), while 
patients with symptomatic gastritis only take additional four-weeks of antacid. 
On recruitment, patients are requested to complete a standard record for a complete medical 
history and demographic data. Additionally, blood sampling for genotyping of CYP2C19 is carried 
out. To assess eradication efficacy and status of ulcer healing, repeated endoscopy with rapid 
urease test, histological examination and culture is performed for peptic ulcer patients at the sixth 
week after the end of anti- H. pylori therapy. Urea breath test is conducted to assess H. pylori 
status in the subjects with gastritis and in peptic ulcer subjects who refuse follow-up endoscopy,. 
Eradication is defined as (1) negative results of both rapid urease test and histology, or (2) a 
negative result of urea breath test. 
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    Finally, the eradication rates by both intention-to-treat and per-protocol analyses, adverse events 
and compliance will be compared between groups by chi-square test, and the host and bacterial 
factors influencing the efficacy of eradication therapy are assessed by multivariate analysis.
Statistical analysis
The primary outcome variable is eradication rate. The secondary outcome variables are the rate 
of adverse events and compliance. Chi-square test with or without Yates correction for continuity 
and Fisher’s exact test are used when appropriate to compare the major outcomes between groups 
using the SPSS program (version 10.1, Chicago, Illinois, USA). A  P value less than 0.05 is 
considered statistically significant. 
    Eradication rates are evaluated by ITT and per-protocol (PP) analyses. ITT analysis includes all 
randomized patients who have taken at least one dose of study medication. Patients whose infection 
status is unknown following treatment are considered treatment failures for the purposes of ITT 
analysis. The PP analysis excludes the patients with unknown H. pylori status following therapy and 
those with major protocol violations. 
    To determine the independent factors affecting the treatment response, Host and bacterial 
parameters are analyzed by univariate analysis. These variables include the following: age (<60 or 
60 years), gender, history of smoking, history of alcohol consumption (<80 g/day or 80 g/day), 
ingestion of coffee (<1 cup/day or  1 cup/day), ingestion of tea ((<1 cup/day or  1 cup/day), 
coexistence of a systemic disease (yes or no), previous history of peptic ulcer disease, endoscopic 
appearance (ulcer or gastritis), CYP2C19 polymorphism, drug compliance (good or poor), and 
antibiotic  susceptibility.  Those  variables  found  to  be  significant  by  univariate  analysis  are 
subsequently assessed by a stepwise logistic regression method to identify independent factors for 
eradication outcome.
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