Clinical trial NCT02646332
Conditions: Helicobacter Pylori Infection
Keywords: Helicobacter pylori Eradication rate
Sponsor: Kaohsiung Veterans General Hospital.
Start date: 2015-12-01; Completion date: 2020-08-31
Enrollment: 248 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Reverse hybrid therapy achieves a higher eradication rate than concomitant therapy remains 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 concomitant therapy remains unanswered.

Arms: arm 1: a 7-day quadruple regimen with dexlansoprazole MR 60 mg once 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 dexlansoprazole MR 60 mg once daily and amoxicillin 1 g twice daily arm 2: dexlansoprazole MR 60 mg once daily, amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice daily for 14 days
Interventions: intervention 1: (dexlan+amox+clar+metr)+(dexlan+amox) intervention 2: dexlan+clarith+amox+metro
Intervention descriptions: intervention 1: a 7-day quadruple regimen with dexlansoprazole MR 60 mg once 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 dexlansoprazole MR 60 mg once daily and amoxicillin 1 g twice daily intervention 2: dexlansoprazole MR 60 mg once daily, amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice daily for 14 days

Protocol documents:
Prot_SAP_000.pdf: 
 
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VGHKS15-CT7-15 
Institution/Department：Kaohsiung Veterans General Hospital 
Principal Investigator (PI)：Prof. Ping-I Hsu  
Research Project Title：Comparing the Efficacy of Reverse Hybrid Therapy and 
Concomitant Therapy 
NCT Number：NCT02646332  
Date of the document：   8   31   2020  （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 reversed the drug administration sequence of hybrid therapy and 
developed a new two-phase one-step treatment — reverse hybrid therapy. The new therapy is 
superior to standard triple therapy for H pylori eradication, but whether it also achieves a high 
eradication rate than sequential or concomitant therapy remains unanswered. Additionally, the 
impacts of reverse hybrid therapy and aforementioned new therapies on gastrointestinal microbiota 
are unclear. 
Aims: The aims of this randomized controlled trial are (1) to compare the efficacies of reverse 
hybrid therapy and concomitant therapy, (2) to investigate the host and bacterial factors predicting 
the treatment outcomes of the two eradication regimens. 
Methods: Consecutive 248 H. pylori-infected subjects are randomly assigned to receive either a 
14-day reverse hybrid therapy or a 14-day concomitant 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 


 
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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) infect more than 50% of humans globally. It is the 
principal cause of chronic gastritis, gastric ulcer, duodenal ulcer, gastric adenocarcinoma and 
gastric mucosa-associated lymphoid tissue lymphoma (MALToma) [1,2]. In most international 
guidelines [3-6], standard triple therapy consisting of a proton-pump inhibitor (PPI), 
clarithromycin and amoxicillin (or metronidazole) for 7 to 14 days is recommended as the 
choice of treatment for first-line therapy of H pylori infection, especially in areas of low 
clarithromycin resistance (< 15%). Recently, the eradication rates of standard triple therapy 
have declined to less than 80% in many countries, largely owing to emerging organism 
resistances [7-10].  Some European studies even reported very poor treatment outcomes of the 
standard therapy with failure rates of 25-60% [11-13]. Several strategies including sequential 
therapy, concomitant therapy and hybrid therapy have therefore been proposed to increase the 
eradication rate [14-16]. 
   Concomitant therapy is another novel regimen proven successful in the presence of 
clarithromycin resistance [15]. It is a 4-drug regimen containing a PPI (standard dose, b.i.d.), 
clarithromycin (500 mg, b.i.d.), amoxicillin (1 g, b.i.d.) and metronidazole (500 mg, b.i.d.) 


 
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which are all given for the entire duration of therapy. This therapy is superior to standard triple 
therapy for H pylori eradication [17]. It is also less complex than sequential therapy as this 
regimen does not involve changing drugs halfway through. A head-to-head non-inferiority trial 
of 10-day sequential and 10-day concomitant therapy showed they were equivalent (93.1% vs 
93.0% by per-protocol analysis) [18]. 
   Recently, we have developed a new anti-H pylori regimen — hybrid therapy , which 
consists of a dual therapy with a PPI (standard dose, b.i.d.) and amoxicillin (1 g, b.i.d.) for 7 
days followed by a quadruple regimen with a PPI (standard dose, b.i.d.), amoxicillin (1 g, 
b.i.d.), clarithromcyin (500 mg, b.i.d.) and metronidazole (500 mg, b.i.d.) for 7 days [16]. The 
novel therapy provided excellent eradication rates of 99% and 97% according to per-protocol 
and intention-to-treat analysis [16]. Several randomized controlled trials subsequently 
demonstrated that hybrid regimens were comparable with or more effective than sequential 
regimens [19-22]. It is important to note that the new therapy has a high efficacy in the 
treatment of H pylori strains harboring dual resistance to clarithromycin and metronidazole. 
Several studies have shown that sequential therapy is ineffective to clear H pylori with dual 
resistance [14]. The prolonging treatment duration of amoxicillin to 14 days in hybrid therapy 
might account for the higher eradication rate in the face of H pylori stains with dual resistance 
to clarithromycin and metronidazole. A study from Italy [20] which compared markedly 
different durations of therapy (14-day hybrid therapy vs 5-day concomitant therapy) showed 
that 14-day hybrid therapy was superior by PP analysis (95.7% vs 85.1%). However, another 


 
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randomized controlled trial showed comparable eradication efficacy between hybrid and 
concomitant therapies [23].  The study also showed that there was a borderline significant 
trend toward higher compliance with hybrid therapy compared with concomitant therapy (99% 
vs 95%) [23]. Many expert recommendations therefore proposed hybrid therapy as a treatment 
option for H pylori in areas with moderate or high clarithromycin resistance [24-27]. 
Switching drugs halfway through the course increases the complexity of an anti-H pylori 
regimen. Reversing the sequence of drug administration (a quadruple regimen followed by a dual 
regimen) simplifies hybrid therapy and make it become a one-step two-phase therapy. We recently 
conducted a  multi-center, randomized controlled trial to compare the efficacies of reverse hybrid 
therapy and standard triple therapy [28]. The data indicated that reverse hybrid therapy achieved a 
higher eradication rate than standard triple therapy (95.5% vs 88.6%) by ITT analysis. 
Currently, whether reverse hybrid therapy is superior to concomitant therapy in H pylori 
eradication remains unanswered. Theoretically, the ideal treatment for H pylori infection should be 
a cheap, highly effective, and well-tolerated therapy. Since the pharmaceutical cost of 14-day 
reverse hybrid therapy is cheaper than 14-day concomitant therapy, the former would be a better 
choice than the latter for H pylori eradication if its eradication rate is superior or non-inferior to that 
of concomitant therapy.We hence conduct the randomized controlled trial are (1) to compare the 
efficacies of 14-day reverse hybrid therapy and 14-day concomitant therapy, (2) to investigate the 
host and bacterial factors predicting the treatment outcomes of the two eradication regimens. 
 


 
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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 248 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 
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 dexlansoprazole MR 
60 mg once 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 dexlansoprazole MR 60 
mg once daily and amoxicillin 1 g twice daily) or a 14-day concomitant therapy (dexlansoprazole 


 
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MR 60 mg once daily, amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, and 
metronidazole 500 mg twice daily for 14 days). All drugs are taken one hour before breakfast or 
dinner. Patients with peptic ulcers in initial endoscopy receive an additional 4-week 
dexlansoprazole MR therapy (60 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.     
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 


 
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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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