14-day Quadruple Hybrid vs. Concomitant Therapies for Helicobacter Pylori Eradication

Condition(s) targeted: Helicobacter Pylori Infection

Intervention: PPI, amoxicillin, metronidazole and clarithromycin (Drug); PPI, amoxicillin, metronidazole and clarithromycin (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Infante, Javier Molina, M.D.

Official(s) and/or principal investigator(s):
Javier Molina-Infante, MD, Principal Investigator, Affiliation: Hospital San Pedro de Alcantara, Caceres, Spain

Overall contact:
Javier Molina-Infante, MD, Phone: 0034627430248, Email: xavi_molina@hotmail.com

Helicobacter pylori (H. pylori) infects approximately 50% of the adult population and is well recognized as the main cause of gastritis, peptic ulcer disease and gastric cancer. The cure of the H. pylori infection prevents recurrence of duodenal and gastric ulcer and improves dyspepsia in a significant proportion of cases, so it is cost-effective.

Eradication therapy has changed over time. Recent meta-analyses have that the current global eradication rate after standard triple therapy (STT) is less than 80%. Several European studies have found even lower eradication rates, with 35-40% of cases resulting in treatment failure, probably due to increased resistance to antibiotics in many geographical areas, principally to clarithromycin. The usually recommended pattern in the American and European (Maastricht III) consensus conferences from 2007 has traditionally been triple therapy, composed by the combination of 2 antibiotics (clarithromycin plus amoxicillin or metronidazole) and a proton pump inhibitor (PPI) for 7-14 days. However, triple therapy was discouraged in settings with high rates of clarithromycin resistance (15-20%) and, as such, new strategies in order to improve the efficacy of first-line treatments are required. Treatment failure increases antibiotic resistant strains, leads to a second treatment and a new diagnostic test to confirm eradication. Unfortunately, it remains unknown whether there is room for improvement in these geographical areas using clarithromycin-containing therapies or switching to bismuth quadruple therapy should be followed instead.

Official title: Phase 4, Prospective, Randomized Study Comparing 14-day Non-bismuth Quadruple "Hybrid" and "Concomitant" Therapies for Helicobacter Pylori Eradication in Settings With High Clarithromycin Resistance

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: "Intention to treat" eradication rates

Secondary outcome:

" Per protocol" eradication rate

Treatment compliance

Number of participants with adverse events

Detailed description: Justification of the study:

Several non-bismuth quadruple clarithromycin-containing regimens have raised over the last decade aiming to substitute standard triple therapy (STT) for first-line H. pylori eradication therapy. Sequential therapy, introduced in Italy, involves a 5-day induction phase with dual therapy (a PPI every 12 hours and amoxicillin 1g every 12 hours), followed immediately by triple therapy for 5 days with a PPI every 12 hours, metronidazole 500 mg every 12 hours and clarithromycin 500 mg every 12 hours. 10-day sequential therapy proved more effectiveness than STT with excellent treatment compliance and minimal side effects. However, the efficacy of sequential therapy seems to be notably impaired by clarithromycin resistance and dual clarithromycin and metronidazole resistance, which is becoming a common scenario in developed countries.

Other interesting and resurfaced therapeutic alternative is the non-bismuth quadruple therapy (NBQT), also called "concomitant" therapy, which includes a PPI, amoxicillin, clarithromycin and a nitroimidazole, all drugs given concurrently and twice daily. It has also demonstrated its superiority over STT and it could be potential replacement for STT as first-line regimen. However, NBQT might have several advantages over sequential therapy, namely, less complexity for both the patient and the physician, twice the duration of all prescribed antibiotics, a proper validation process worldwide and a higher efficacy over sequential therapy for both clarithromycin and dual-resistant H. pylori. Finally, another recent innovation is the 14-day quadruple clarithromycin-based regimen, so-called the sequential-concomitant "hybrid" therapy, which involves PPI and amoxicillin for 7 days plus a 7-day course of NBQT. Outstanding cure rates close to 100% have been recently reported using this scheme, thereby requiring further consideration.

Therefore it is necessary to make a controlled clinical trial to directly compare NBQT "hybrid" versus "concomitant" therapy in settings with documented high clarithromycin resistance rates. In order to maximize the efficacy of eradication regimens, it would be necessary to extend duration to 14 days and using high-dose PPI (omeprazole 40 mg bid). The results of this study will conclude whether there is still room for clarithromycin-containing regimens in H. pylori eradication even in settings with high antibiotic resistance rates.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients with dyspepsia or peptic gastroduodenal ulcer for whom eradication treatment

is indicated.

- Requirement of confirmation of the diagnosis of H. pylori infection by at least one

positive test out of the following: breath test, histology, rapid urease test or culture.

Exclusion Criteria:

- Age less than 18 years.

- Advanced chronic disease or any other pathology that prevents attending controls and

follow up.

- Allergy to any of the antibiotics in the treatment.

- Previous gastric surgery

- Pregnancy and lactation.

- History of alcohol or drug abuse.

- Previous eradication treatment.

- Consumption of antibiotics or bismuth salts during the last 4 weeks

Javier Molina-Infante, MD, Phone: 0034627430248, Email: xavi_molina@hotmail.com

Azienda Ospedaliera Universitaria, Napoli, Italy; Recruiting
Marco Romano, MD,PhD, Email: marco.romano@unina2.it
Marco Romano, Principal Investigator
Antonio Cuomo, Sub-Investigator
Riccardo Marmo, Sub-Investigator
Gerardo Nardone, Sub-Investigator
Roberto Lamanda, Sub-Investigator

Hospital San Pedro de Alcantara, Caceres 10003, Spain; Recruiting
Javier Molina-Infante, MD, Email: xavi_molina@hotmail.com
Javier Molina-Infante, MD, Principal Investigator
Belen Perez-Gallardo, MD, Sub-Investigator
Miguel Fernandez-Bermejo, MD, Sub-Investigator

Hospital de Merida, Merida, Badajoz, Spain; Recruiting
Liliana Pozzati, MD, Email: santelmo0054@hotmail.com
Liliana Pozzati, MD, Principal Investigator
Marta Gata-Cuadrado, Sub-Investigator

Hospital Virgen del Puerto, Plasencia, Caceres, Spain; Recruiting
Elena G Abadia, Email: elenagabadia@hotmail.com
Elena G Abadia, Principal Investigator

Related publications:

Malfertheiner P, Megraud F, O'morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ. Current concepts in the management of Helicobacter pylori infection - The Maastricht III Consensus Report. Gut. 2007 Jan 17; [Epub ahead of print]

Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007 Aug;102(8):1808-25. Epub 2007 Jun 29.

Graham DY, Shiotani A. New concepts of resistance in the treatment of Helicobacter pylori infections. Nat Clin Pract Gastroenterol Hepatol. 2008 Jun;5(6):321-31. Epub 2008 Apr 29. Review.

Mégraud F. H pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut. 2004 Sep;53(9):1374-84. Review. No abstract available.

Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010 Aug;59(8):1143-53. Epub 2010 Jun 4. Review.

Zullo A, De Francesco V, Hassan C, Morini S, Vaira D. The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis. Gut. 2007 Oct;56(10):1353-7. Epub 2007 Jun 12. Review.

Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatment. Ann Intern Med. 2008 Jun 17;148(12):923-31. Epub 2008 May 19. Erratum in: Ann Intern Med. 2008 Sep 16;149(6):439.

Tong JL, Ran ZH, Shen J, Xiao SD. Sequential therapy vs. standard triple therapies for Helicobacter pylori infection: a meta-analysis. J Clin Pharm Ther. 2009 Feb;34(1):41-53.

Gatta L, Vakil N, Leandro G, Di Mario F, Vaira D. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol. 2009 Dec;104(12):3069-79; quiz 1080. Epub 2009 Oct 20. Review.

Gisbert JP, Calvet X, O'Connor A, Mégraud F, O'Morain CA. Sequential therapy for Helicobacter pylori eradication: a critical review. J Clin Gastroenterol. 2010 May-Jun;44(5):313-25. Review.

Prieto-Jimenez CA, Cardenas VM, Fischbach LA, Mulla ZD, Rivera JO, Dominguez DC, Graham DY, Ortiz M. Double-blind randomized trial of quadruple sequential Helicobacter pylori eradication therapy in asymptomatic infected children in El Paso, Texas. J Pediatr Gastroenterol Nutr. 2011 Mar;52(3):319-25.

Patrick B, Nicolas K, Giuseppina O, Assad S, Laurence M, Yvette MD, Josette R, Samy C, Michèle S. Sequential Therapy vs. Tailored Triple Therapies For Helicobacter Pylori Infection In Children: A Prospective, Open-label, Multi-center Study. J Pediatr Gastroenterol Nutr. 2011 Jun 21; [Epub ahead of print]

Molina-Infante J, Perez-Gallardo B, Fernandez-Bermejo M, Hernandez-Alonso M, Vinagre G, Dueñas C, Mateos-Rodriguez JM, Gonzalez-Garcia G, Abadia EG, Gisbert JP. Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication. Aliment Pharmacol Ther. 2010 May;31(10):1077-84. Epub 2010 Feb 20.

Choi WH, Park DI, Oh SJ, Baek YH, Hong CH, Hong EJ, Song MJ, Park SK, Park JH, Kim HJ, Cho YK, Sohn CI, Jeon WK, Kim BI. [Effectiveness of 10 day-sequential therapy for Helicobacter pylori eradication in Korea]. Korean J Gastroenterol. 2008 May;51(5):280-4. Korean.

Romano M, Cuomo A, Gravina AG, Miranda A, Iovene MR, Tiso A, Sica M, Rocco A, Salerno R, Marmo R, Federico A, Nardone G. Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial. Gut. 2010 Nov;59(11):1465-70.

Wu DC, Hsu PI, Wu JY, Opekun AR, Kuo CH, Wu IC, Wang SS, Chen A, Hung WC, Graham DY. Sequential and concomitant therapy with four drugs is equally effective for eradication of H pylori infection. Clin Gastroenterol Hepatol. 2010 Jan;8(1):36-41.e1. Epub 2009 Oct 3.

Sirimontaporn N, Thong-Ngam D, Tumwasorn S, Mahachai V. Ten-day sequential therapy of Helicobacter pylori infection in Thailand. Am J Gastroenterol. 2010 May;105(5):1071-5. Epub 2009 Dec 15.

Mahachai V, Sirimontaporn N, Tumwasorn S, Thong-Ngam D, Vilaichone RK. Sequential therapy in clarithromycin-sensitive and -resistant Helicobacter pylori based on polymerase chain reaction molecular test. J Gastroenterol Hepatol. 2011 May;26(5):825-8.

Vaira D, Zullo A, Vakil N, Gatta L, Ricci C, Perna F, Hassan C, Bernabucci V, Tampieri A, Morini S. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med. 2007 Apr 17;146(8):556-63. Summary for patients in: Ann Intern Med. 2007 Apr 17;146(8):I20.

Gisbert JP, Calvet X. Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobater pylori. Aliment Pharmacol Ther. 2011 Sep;34(6):604-17. Epub 2011 Jul 11. Review.

Hsu PI, Wu DC, Wu JY, Graham DY. Modified sequential Helicobacter pylori therapy: proton pump inhibitor and amoxicillin for 14 days with clarithromycin and metronidazole added as a quadruple (hybrid) therapy for the final 7 days. Helicobacter. 2011 Apr;16(2):139-45.

Malfertheiner P, Bazzoli F, Delchier JC, Celiñski K, Giguère M, Rivière M, Mégraud F; Pylera Study Group. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet. 2011 Mar 12;377(9769):905-13. Epub 2011 Feb 21.

Dore MP, Farina V, Cuccu M, Mameli L, Massarelli G, Graham DY. Twice-a-day bismuth-containing quadruple therapy for Helicobacter pylori eradication: a randomized trial of 10 and 14 days. Helicobacter. 2011 Aug;16(4):295-300.

Villoria A, Garcia P, Calvet X, Gisbert JP, Vergara M. Meta-analysis: high-dose proton pump inhibitors vs. standard dose in triple therapy for Helicobacter pylori eradication. Aliment Pharmacol Ther. 2008 Oct 1;28(7):868-77. Epub 2008 Jul 17.

Starting date: September 2011
Last updated: December 27, 2012