Comparison Between Hybrid, Reverse Hybrid, and Non-Bismuth Levofloxacin Quadruple Regimens for Helicobacter Pylori Infection in Egypt: A Randomized Controlled Trial
Phase: PHASE4
Conditions: Helicobacter Pylori Infection
Sponsor: Ayman Magd Eldin Mohammad Sadek

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Zagazig University.  
Faculty of Medicine. 
Internal Medicine Department. 
Comparison between Hybrid, Reverse Hybrid, and Non-Bismuth 
Levofloxacin Quadruple Regimens for Helicobacter Pylori 
Infection in Egypt: A Randomized Controlled Trial  
 
Ayman F. Elsayed*, Ayman M.E.M. Sadek*, Walid A.R. Abdelhamid* 
* Lecturer of Internal Medicine (MD), Faculty of Human Medicine, Zagazig 
University, Zagazig, Egypt 
Approval Date: 
9-1-2019 
Corresponding Author: 
Name: Ayman M.E.M. Sadek 
Address: Shoubak Basta – Zagazig – Shakia - Egypt 
Phone numbers: +201221387405, +201114480339 (WhatsApp) 
Postal code: 44519 
ORCID ID: 0000-0002-1095-1411 
Researcher ID: R-5458-2017  
E-mail address: amedms@gmail.com, ayman.sadek@zu.edu.eg 

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Introduction 
Although the decreasing prevalence of Helicobacter Pylori (H. Pylori) worldwide, 
it remains high in the developing countries [1]. According to the most recent 
studies, the overall prevalence of H. Pylori in the developing countries is 50.8%, 
with the highest one presented in Africa (79.1%) [2, 3]. 
Unfortunately, the data on the prevalence of H. Pylori, are not available from all 
the countries of Africa. There is a paucity of information about the magnitude of 
the problem in Egypt, according to the few available studies, the prevalence is 
ranging from 71.7-91.7% [4, 5]. 
The importance of H. Pylori infection lies in the major role in chronic gastritis, 
gastric ulcer, and duodenal ulcer, up to gastric adenocarcinoma, and gastric 
mucosa-associated lymphoid tissue lymphoma [6]. 
Diagnosis of H. Pylori can be through invasive tests, which are cumbersome and 
expensive despite their high sensitivity and specificity. On the contrary, there are 
more easily and cheaper non-invasive tests, especially H. Pylori stool antigen 
and urea breath test have a higher sensitivity than serology [7]. 
The decreasing eradication rate of the standard triple therapy (STT) below 80% 
due to the emergence of resistant strains to Clarithromycin, raise the need for 
newer therapies that provide higher efficacy, and in the same time, better safety 
and compliance [8]. 
Bismuth-containing quadruple therapy came as the treatment of choice that 
avoids Clarithromycin use [9], but it was a non-reasonable option for the 
countries that are lacking in bismuth salts and/or tetracycline [10], beside of the 

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complex administration and low safety [11]. It raises the era of the competing 
sequential and concomitant non-bismuth (clarithromycin containing) quadruple 
treatments [12]. 
A novel two-step (dual-quadruple) treatment called the hybrid therapy (HT), 
which is actually a combined sequential and concomitant therapy, with a lower 
cost and better efficacy [13]. 
However, the adding of two drugs in the last seven days of the therapy may 
confuse the patient, making him less willing to complete the treatment that 
promote the idea of reversing the sequence (quadruple-dual) in what is called the 
reverse hybrid therapy (RHT), to simplify the treatment in one-step two-phase 
treatment [14]. 
Another non-Clarithromycin non-Bismuth quadruple therapy that is less complex 
and safer than bismuth quadruple therapy, which is called Levofloxacin 
quadruple 
therapy 
that 
contains 
levofloxacin, omeprazole, nitazoxanide, 
and doxycycline (LOND), showed promising results on the level of the cure rate 
and low drug resistance profile [15, 16]. 
 

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Rational 
    As Helicobacter pylori is a common infection and a leading cause of gastric 
and duodenal ulcers with an increased incidence of gastric cancer, so we need 
an effective regimen as a first line in treatment of Helicobacter pylori. 
Research questions 
Which of the Hybrid, Reverse hybrid, and Levofloxacin quadruple therapies 
are more effective as a first-line eradication regimen for Helicobacter pylori in 
Egypt? 
Hypothesis 
The expected result of this study that Hybrid therapy is more effective than 
Reverse Hybrid and Levofloxacin quadruple therapies as a first-line eradication 
regimen for Helicobacter pylori infection in Egypt. 
Aim of Work 
We are aiming here to compare the Hybrid, Reverse hybrid, and Levofloxacin 
quadruple therapies as first-line therapy, trying to reach the safest, cost-effective, 
and compliance-inducing regimen in Egypt. 
Objectives 
 To assess the efficacy of Hybrid, reverse hybrid, and Levofloxacin 
quadruple therapies as a first line eradication regimen for Helicobacter 
pylori infection in Egypt. 
 To evaluate the safety of each regimen. 
 To determine which regimen has the best patient’s compliance. 
 

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Subjects and Methods 
Technical Design 
A) The site of study: 
The study will be conducted in Internal medicine department in Zagazig 
University Hospitals. 
B) Sample size: 
Assuming that the eradication rate in patients receiving Hybrid therapy is 
91% versus 78.3% in Reverse Hybrid therapy. So, the sample size is 309 
(103 in each group), using OPEN EPI at power 80% and C.I 95%. 
C) Inclusion criteria: 
1- Age more than 18 years.  
2- Both gender. 
3- Patient’s approval to participate in the study. 
4- Patients with positive Helicobacter pylori antigen in the stool with no 
previous treatment for Helicobacter pylori. 
D) Exclusion criteria 
1- Age < 18 years.  
2- Patients who refuse to participate in the study. 
3- Patients with previous treatment for Helicobacter pylori. 
4- Patients with known hypersensitivity to drugs used in regimens. 
Tools of data collection 
The following procedures were done to all enrollees: 
1- Medical history to all patients.  

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2- Complete clinical examination. 
3- The fecal antigen test (FAT) which identifies H. pylori antigen in the 
stool by enzyme immunoassay was positive in all participants. 
Operational design 
 This is a randomized controlled (interventional) study conducted at 
Zagazig University Hospital, internal medicine department clinic after 
informed consent. All the patients are positive for H. pylori fecal antigen 
test.  
 Steps of performance: (309) patients will be chosen from the Internal 
Medicine Department clinic, grouped into 3 groups: 
o Group 1: (103) patients will receive reverse hybrid regimen in the 
form of clarithromycin 500mg bid, omeprazole 20 mg bid, 
amoxicillin 1gm bid, and metronidazole 500 mg tid for 1 week, 
followed by omeprazole 20 mg bid, and amoxicillin 1gm bid in the 
2nd week. 
o Group2: (103) patients will receive hybrid regimen in the form of 
omeprazole 20 mg bid, and amoxicillin 1gm bid in the 1st week, 
then clarithromycin 500mg bid, omeprazole 20 mg bid, amoxicillin 
1gm bid, and metronidazole 500 mg tid in the 2nd week. 
o Group3: (103) patients will receive Levofloxacin quadruple regimen 
(LOAD) in the form of nitazoxanide 500 mg bid, levofloxacin 250 
mg QD, omeprazole 40 mg QD, and doxycycline 100 mg QD for 10 
days 

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 Retesting by the fecal antigen test (FAT) after stopping the regimen by at 
least one month and withholding proton pump inhibitors for 2 weeks.  
Administrative design 
 Approval of medical department. 
 Approval of the ethical committee in the faculty of medicine. 
 Institutional Review Board (IRB) approval. 
 Consent from the patient sheet. 
Statistical analysis plan  
The software SPSS (SPSS Inc., Chicago, Illinois, USA) version 19 for Windows 
will be used. Quantitative variables will be described using their means and 
standard deviations (Mean ± SD). Categorical variables will be described using 
their absolute frequencies. 
Comparison of categorical data will be performed using the Chi-square test and 
Fisher exact test when appropriate. Kolmogorov-Smirnov's (distribution-type) and 
Levene's (homogeneity of variances) tests will be used to verify assumptions for 
use in parametric tests. All normally distributed data will be interpreted using 
One-Way ANOVA F test. A nonparametric test (Kruskal-Wallis H Test) will be 
used to compare means when data is not normally distributed. A two-sided 
(α=2) p<0.05 will be considered significant. Additional tests according to the 
results will be used when appropriate. 
 
 
 

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