Comparison Between Quadruple Regimens for Helicobacter Pylori Infection in Egypt

• ClinicalTrials.gov Identifier: NCT04039412
• Recruitment Status: Completed
• First Posted: July 31, 2019
• Results First Posted: November 26, 2019
• Last Update Posted: November 26, 2019
• Sponsor: Ayman Magd Eldin Mohammad Sadek
• Information provided by (Responsible Party): Ayman Magd Eldin Mohammad Sadek, Zagazig University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Helicobacter Pylori Infection
• Interventions: Drug: Hybrid regimen; Drug: Reverse hybrid regimen; Drug: Levofloxacin quadruple regimen
• Enrollment: 330

Participant Flow

Recruitment Details	We conducted an interventional randomized trial at the internal medicine department clinic, Zagazig University Hospital, Zagazig, Egypt, in the period from July 2018 to June 2019. We allocated the participants attending the clinic by simple randomization over the three treatment groups.
Pre-assignment Details

Arm/Group Title	(1) Reverse Hybrid Regimen	(2) Hybrid Regimen	(3) Levofloxacin Quadruple Regimen
Arm/Group Description	clarithromycin 500mg bid, omeprazole 20mg bid, amoxicillin 1gm bid, and metronidazole 500mg tid for 1 week, followed by omeprazole 20mg bid, and amoxicillin 1gm bid in the 2nd week. Reverse hybrid regimen: one-step two-phase (quadruple-dual) treatment	omeprazole 20mg bid, and amoxicillin 1gm bid in the 1st week, then clarithromycin 500mg bid, omeprazole 20mg bid, amoxicillin 1gm bid, and metronidazole 500mg tid in the 2nd week. Hybrid regimen: two-step (dual-quadruple) treatment	levofloxacin 250mg QD, omeprazole 40mg QD, nitazoxanide 500mg bid, and doxycycline 100mg QD for 10 days. (LOAD) Levofloxacin quadruple regimen: non-Clarithromycin non-Bismuth quadruple therapy
Period Title: Overall Study
Started	110	110	110
Completed	109	107	108
Not Completed	1	3	2

Baseline Characteristics

Arm/Group Title		(1) Reverse Hybrid Regimen	(2) Hybrid Regimen	(3) Levofloxacin Quadruple Regimen	Total
Arm/Group Description		clarithromycin 500mg bid, omeprazole 20mg bid, amoxicillin 1gm bid, and metronidazole 500mg tid for 1 week, followed by omeprazole 20mg bid, and amoxicillin 1gm bid in the 2nd week. Reverse hybrid regimen: one-step two-phase (quadruple-dual) treatment	omeprazole 20mg bid, and amoxicillin 1gm bid in the 1st week, then clarithromycin 500mg bid, omeprazole 20mg bid, amoxicillin 1gm bid, and metronidazole 500mg tid in the 2nd week. Hybrid regimen: two-step (dual-quadruple) treatment	levofloxacin 250mg QD, omeprazole 40mg QD, nitazoxanide 500mg bid, and doxycycline 100mg QD for 10 days. (LOAD) Levofloxacin quadruple regimen: non-Clarithromycin non-Bismuth quadruple therapy	Total of all reporting groups
Overall Number of Baseline Participants		110	110	110	330
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	110 participants	110 participants	110 participants	330 participants
		32.05 (9.772)	32.31 (9.409)	32.44 (9.713)	32.27 (9.604)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	110 participants	110 participants	110 participants	330 participants
	Female	57 51.8%	58 52.7%	55 50.0%	170 51.5%
	Male	53 48.2%	52 47.3%	55 50.0%	160 48.5%
Race and Ethnicity Not Collected [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	0 participants	0 participants	0 participants	0 participants
					0
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Egypt	Number Analyzed	110 participants	110 participants	110 participants	330 participants
		110	110	110	330

Outcome Measures

1. Primary Outcome

Title	Percentage of Helicobacter Pylori Infection Cure
Description	Measuring the curative rate of each regimen by a fecal antigen test
Time Frame	40-44 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	(1) Reverse Hybrid Regimen	(2) Hybrid Regimen	(3) Levofloxacin Quadruple Regimen
Arm/Group Description:	clarithromycin 500mg bid, omeprazole 20 mg bid, amoxicillin 1gm bid, and metronidazole 500mg tid for 1 week, followed by omeprazole 20 mg bid, and amoxicillin 1gm bid in the 2nd week	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 500mg tid in the 2nd week	levofloxacin 250mg QD, omeprazole 40mg QD, nitazoxanide 500mg bid, and doxycycline 100mg QD for 10 days
Overall Number of Participants Analyzed	110	110	110
Measure Type: Count of Participants; Unit of Measure: Participants
	102 92.7%	101 91.8%	91 82.7%

2. Primary Outcome

Title	Incidence of Treatment-Emergent Adverse Events
Description	Questionnaire to measure the number of Participants with Treatment-Emergent Adverse Events
Time Frame	10-14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	(1) Reverse Hybrid Regimen	(2) Hybrid Regimen	(3) Levofloxacin Quadruple Regimen
Arm/Group Description:	clarithromycin 500mg bid, omeprazole 20 mg bid, amoxicillin 1gm bid, and metronidazole 500mg tid for 1 week, followed by omeprazole 20 mg bid, and amoxicillin 1gm bid in the 2nd week	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 500mg tid in the 2nd week	levofloxacin 250mg QD, omeprazole 40mg QD, nitazoxanide 500mg bid, and doxycycline 100mg QD for 10 days
Overall Number of Participants Analyzed	110	110	110
Measure Type: Count of Participants; Unit of Measure: Participants
	49 44.5%	58 52.7%	44 40.0%

3. Secondary Outcome

Title	Rate of Helicobacter Pylori Treatment Completion
Description	Questionnaire to evaluate the compliance with each treatment regimen
Time Frame	10-14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	(1) Reverse Hybrid Regimen	(2) Hybrid Regimen	(3) Levofloxacin Quadruple Regimen
Arm/Group Description:	109 participants in per-protocol analysis (99.1%)	107 participants in per-protocol analysis (97.3%)	108 participants in per-protocol analysis (98.2%)
Overall Number of Participants Analyzed	110	110	110
Measure Type: Count of Participants; Unit of Measure: Participants
	109 99.1%	107 97.3%	108 98.2%

Adverse Events

Time Frame	We followed up the occurrence of adverse events after one week of therapy, at the end of treatment, and Up to 45 days.
Adverse Event Reporting Description	We divided the severity of adverse event according to the extent of daily activities limitation, into mild, moderate, and severe (no limitation, partial limitation, and profound limitation respectively).
Arm/Group Title	(1) Reverse Hybrid Regimen		(2) Hybrid Regimen		(3) Levofloxacin Quadruple Regimen
Arm/Group Description	clarithromycin 500mg bid, omeprazole 20 mg bid, amoxicillin 1gm bid, and metronidazole 500mg tid for 1 week, followed by omeprazole 20 mg bid, and amoxicillin 1gm bid in the 2nd week		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 500mg tid in the 2nd week		levofloxacin 250mg QD, omeprazole 40mg QD, nitazoxanide 500mg bid, and doxycycline 100mg QD for 10 days
All-Cause Mortality
	(1) Reverse Hybrid Regimen		(2) Hybrid Regimen		(3) Levofloxacin Quadruple Regimen
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/109 (0.00%)		0/107 (0.00%)		0/108 (0.00%)
Serious Adverse Events
	(1) Reverse Hybrid Regimen		(2) Hybrid Regimen		(3) Levofloxacin Quadruple Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/109 (0.00%)		0/107 (0.00%)		0/108 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	(1) Reverse Hybrid Regimen		(2) Hybrid Regimen		(3) Levofloxacin Quadruple Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/110 (44.55%)		58/110 (52.73%)		44/110 (40.00%)
Gastrointestinal disorders
Gastrointestinal symptoms †	41/110 (37.27%)	41	50/110 (45.45%)	50	37/110 (33.64%)	37
General disorders
General symptoms †	8/110 (7.27%)	8	8/110 (7.27%)	8	7/110 (6.36%)	7
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. Ayman Fathy Elsayed
• Organization: Zagazig University-Faculty of Human Medicine
• Phone: +201125020593
• EMail: aymanf28@yahoo.com

Publications:

Torres J, Pérez-Pérez G, Goodman KJ, Atherton JC, Gold BD, Harris PR, la Garza AM, Guarner J, Muñoz O. A comprehensive review of the natural history of Helicobacter pylori infection in children. Arch Med Res. 2000 Sep-Oct;31(5):431-69. Review.

Zamani M, Ebrahimtabar F, Zamani V, Miller WH, Alizadeh-Navaei R, Shokri-Shirvani J, Derakhshan MH. Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. Aliment Pharmacol Ther. 2018 Apr;47(7):868-876. doi: 10.1111/apt.14561. Epub 2018 Feb 12.

Hooi JKY, Lai WY, Ng WK, Suen MMY, Underwood FE, Tanyingoh D, Malfertheiner P, Graham DY, Wong VWS, Wu JCY, Chan FKL, Sung JJY, Kaplan GG, Ng SC. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology. 2017 Aug;153(2):420-429. doi: 10.1053/j.gastro.2017.04.022. Epub 2017 Apr 27. Review.

El Dine SS, Mubarak M, Salama R, El Raziky M, El Sherbiny E, Zakaria S, Zakaria MS. Low Seroprevalence of anti-CagA antibodies inspite of high seroprevalence of anti-H. Pylori antibodies in rural Egyptian community. Research Journal of Medicine and Medical Sciences. 2008; 3(2):118-23.

Diab M, El-Dine SS, Aboul-Fadl L, Shemis M, Omran Z, Badawi A, El-Ghannam M, El-Ray A, Fam N, El-Defrawy I, El-Sherbini E. Helicobacterpylori cag pathogenicity island genes among dyspeptic patients with chronic gastritis. Egypt J Med Microbiol. 2009; 18:43-53.

Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002 Oct 10;347(15):1175-86. Review.

Garza-González E, Perez-Perez GI, Maldonado-Garza HJ, Bosques-Padilla FJ. A review of Helicobacter pylori diagnosis, treatment, and methods to detect eradication. World J Gastroenterol. 2014 Feb 14;20(6):1438-49. doi: 10.3748/wjg.v20.i6.1438. Review.

Huang YK, Wu MC, Wang SS, Kuo CH, Lee YC, Chang LL, Wang TH, Chen YH, Wang WM, Wu DC, Kuo FC. Lansoprazole-based sequential and concomitant therapy for the first-line Helicobacter pylori eradication. J Dig Dis. 2012 Apr;13(4):232-8. doi: 10.1111/j.1751-2980.2012.00575.x.

Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F, Gensini GF, Gisbert JP, Graham DY, Rokkas T, El-Omar EM, Kuipers EJ; European Helicobacter Study Group. Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. Gut. 2012 May;61(5):646-64. doi: 10.1136/gutjnl-2012-302084.

Georgopoulos SD, Papastergiou V, Karatapanis S. Helicobacter pylori Eradication Therapies in the Era of Increasing Antibiotic Resistance: A Paradigm Shift to Improved Efficacy. Gastroenterol Res Pract. 2012;2012:757926. doi: 10.1155/2012/757926. Epub 2012 Jun 19.

Liou JM, Fang YJ, Chen CC, Bair MJ, Chang CY, Lee YC, Chen MJ, Chen CC, Tseng CH, Hsu YC, Lee JY, Yang TH, Luo JC, Chang CC, Chen CY, Chen PY, Shun CT, Hsu WF, Hu WH, Chen YN, Sheu BS, Lin JT, Wu JY, El-Omar EM, Wu MS; Taiwan Gastrointestinal Disease and Helicobacter Consortium. Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial. Lancet. 2016 Nov 12;388(10058):2355-2365. doi: 10.1016/S0140-6736(16)31409-X. Epub 2016 Oct 18.

Malfertheiner P, Megraud F, O'Morain CA, Gisbert JP, Kuipers EJ, Axon AT, Bazzoli F, Gasbarrini A, Atherton J, Graham DY, Hunt R, Moayyedi P, Rokkas T, Rugge M, Selgrad M, Suerbaum S, Sugano K, El-Omar EM; European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut. 2017 Jan;66(1):6-30. doi: 10.1136/gutjnl-2016-312288. Epub 2016 Oct 5.

Liatsos C, Georgopoulos SD. Helicobacter pylori best treatment approach: should a national consensus be the best consensus? Ann Gastroenterol. 2017;30(6):704-706. doi: 10.20524/aog.2017.0183. Epub 2017 Aug 2.

Hsu PI, Tsay FW, Graham DY, Tsai TJ, Tsai KW, Kao JY, Peng NJ, Kuo CH, Kao SS, Wang HM, Lin TF, Wu DC; Taiwan Acid-related Disease (TARD) Study Group. Equivalent Efficacies of Reverse Hybrid and Bismuth Quadruple Therapies in Eradication of Helicobacter pylori Infection in a Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2018 Sep;16(9):1427-1433. doi: 10.1016/j.cgh.2018.03.031. Epub 2018 Mar 31.

Basu PP, Rayapudi K, Pacana T, Shah NJ, Krishnaswamy N, Flynn M. A randomized study comparing levofloxacin, omeprazole, nitazoxanide, and doxycycline versus triple therapy for the eradication of Helicobacter pylori. Am J Gastroenterol. 2011 Nov;106(11):1970-5. doi: 10.1038/ajg.2011.306. Epub 2011 Oct 11.

Abd-Elsalam S, Kobtan A, El-Kalla F, Elkhalawany W, Nawasany SE, Saif SA, Yousef M, Ali LA, Soliman S, Mansour L, Habba E, Soliman H, Rizk F, Shehata MA. A 2-week Nitazoxanide-based quadruple treatment as a rescue therapy for Helicobacter pylori eradication: A single center experience. Medicine (Baltimore). 2016 Jun;95(24):e3879. doi: 10.1097/MD.0000000000003879. Erratum in: Medicine (Baltimore). 2016 Aug 07;95(31):e5074.

• Responsible Party: Ayman Magd Eldin Mohammad Sadek, Zagazig University
• ClinicalTrials.gov Identifier: NCT04039412
• Other Study ID Numbers: ZU-IRB#5089
• First Submitted: July 4, 2019
• First Posted: July 31, 2019
• Results First Submitted: September 22, 2019
• Results First Posted: November 26, 2019
• Last Update Posted: November 26, 2019