Clinical trial NCT02959255: 10-day Versus 14-day Concomitant PAMC as First-line Treatment Strategy for the Eradication of H. Pylori Infection
Official title: A Greek, Single Center, Randomized, Double Blind Controlled Clinical Study Comparing the 10-day Versus the 14-day Concomitant Proton Pump Inhibitor [PPI] + Amoxicillin + Metronidazole + Clarithromycin (PAMC) Therapeutic Scheme as First-line Treatment Strategy for the Eradication of H. Pylori Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Helicobacter Pylori Infection
Lead sponsor: Elpen Pharmaceutical Co. Inc.
Sponsor class: INDUSTRY
First posted: 2016-11-09
Enrollment: 364
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Helicobacter pylori (H. pylori) infection is highly associated with gastrointestinal disorders, including peptic ulcer disease, gastric cancer, and gastric mucosa associated lymphoid tissue lymphoma.1 In 1994, H. pylori was classified as a group carcinogen by the International Agency for Research on Cancer. Since then, many consensus conferences and clinical guidelines worldwide have been established for the treatment of H. pylori infection.

Despite H. pylori infecting an estimated 50% of the global population,there is no universally effective regimen in everyday clinical practice. The current European Helicobacter Study Group Guidelines for the first line empirical treatment of the H. pylori infection propose a variety of treatment strategies, as optimal treatment of H. pylori infection requires careful attention to local antibiotic resistance and eradication patterns. Most recently, the Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults strongly recommended that all H. pylori eradication regimens now be given for 14 days. Recommended first-line strategies include concomitant nonbismuth quadruple therapy (proton pump inhibitor \[PPI\] + amoxicillin + metronidazole + clarithromycin \[PAMC\]) and traditional bismuth quadruple therapy (PPI + bismuth + metronidazole + tetracycline \[PBMT\]).The aforementioned statement by an international working group of specialists chosen by the Canadian Association of Gastroenterology is of the outmost importance, especially in countries with increased antibiotic resistance, like Greece, with resistance rates \>20% to clarithromycin and \>40% to metronidazole.

Detailed description: In Greece, while the efficacy of the 10-day concomitant PAMC scheme has been recently established,to our knowledge no head-to-head comparison evaluating treatment time (10 versus 14 days) of the same therapeutic regimen has been tried out. We decided to conduct a randomized double blind controlled clinical study comparing the 10-day versus the 14-day concomitant PAMC therapeutic scheme as first-line treatment strategy for the eradication of H. pylori infection, in a country of increased dual resistance to clarithromycin and metronidazole (where bismuth is unavailable). The primary end point of our study will be treatment efficacy (primary and secondary antibiotic resistance), while secondary end points will be patient compliance and safety.

This open labeled prospective randomized trial will be held at the Army Share Fund Hospital (NIMTS), in Athens, Greece, and will be conducted by the Hospital's Department of Gastroenterology. Written informed consent will obtained from all participants before enrollment. The study must be approved before hand by the Institutional Review Board of Hospital.

Interventions A physician will be recruited so as to obtain the patients' demographic data and medical history. Using sealed envelopes, eligible patients will be randomized in two groups, with a research assistant assigning the therapies according to the treatment allocations kept in the envelopes. In the first group, patients will be assigned to a 10-day concomitant PAMC therapy (40mg esomeprazole twice daily, 500mg clarithromycin twice daily, 1gr amoxicillin twice daily, and 500mg metronidazole twice daily). In the second group, patients will be assigned to the same concomitant PAMC therapy for 14days. Each envelope will contain precise written instructions regarding the treatment schedule, dosing, and time of medication ingestion, while further instructions will be available, if needed, via the telephone.

Follow-up and outcome To confirm compliance, all patients will be asked to bring their remaining medication 5 days after the end of the treatment where we will count the rest of their pills. Patients with a compliance \<80% will be excluded from the study per protocol (PP) analysis. Patients will also be interviewed for reasons responsible for missing any doses of the regimens, as well as for the occurrence of any new or worsened medical conditions that led them to seek medical attention. Adverse events will be classified as minor or major, with the later leading to discontinuation of the treatment.

Four weeks after the treatment period (with no administration of PPIs or any antibiotics), we will confirm H. pylori eradication using C13-UBT by a staff member who will be blind to the eradication arm of each patient. In case of treatment failure, a repeated endoscopy will be performed with biopsy specimens being taken (two from the antrum and two from the body of the stomach). Biopsy specimens will be cultured and antibiotic susceptibility will be determined for amoxicillin, tetracycline, clarithromycin, metronidazole, and levofloxacin with the aid of the agar dilution test, according to the standard European protocol.14,15 The microbiologist who will be performing the agar dilution test will be blinded to the treatment. If first-line eradication therapy fails, second-line therapy will be administered, according to antibiotic susceptibility.

Statistical analysis In this study, a clinically significant difference for eradication between the two groups will be 15%. In order to achieve 80% power for detecting this difference, along with an alpha level of 0.05 and an allocation ratio of 1:1, we calculated a needed sample of 364 patients. Since this is a convenient clinical sample, the study will be terminated either by reaching this number of patients or by the study's timeline limitation. Baseline characteristics will be compared and the difference of the observed eradication rates between the study groups will be assessed. The results of this study will be analyzed in an intention to treat (ITT) and a PP population. The ITT analysis will include all randomized patients who will have taken at least one dose of the study medication (regardless of compliance). The patients whose infection statuses will be unknown following treatment will be considered treatment failures for the purposes of the ITT analysis. The PP analysis will include patients with at least 80% compliance (excluding the patients with unknown H. pylori status following therapy and those with major protocol violations).

Eligibility criteria: Inclusion Criteria:

* age \>18 or \<80 years
* consecutive newly diagnosed H. pylori-infected patients
* endoscopically proven peptic ulcer disease or non-ulcer dyspepsia
* H. pylori infection will be established by at least one positive test among C13-urea breath test (UBT), rapid urease test, and gastric histology.
* patients who have signed the Informed Consent
* patients who will be compliant to study procedures

Exclusion Criteria:

* age \<18 or \>80 years.
* previous H. pylori eradication therapy
* known allergic history to any of the medications used in our study
* pregnancy or lactation
* ingestion of antibiotics within the prior 4 weeks
* patients with previous gastric surgery
* the coexistence of serious concomitant illness which would not allow patients' compliance (i.e., malignant neoplasms)
* addiction to alcohol or illicit and recreational drugs
* patients who have not signed Informed Consent
* patients who will not comply with study procedures

Primary outcomes:
measure: Helicobacter Pylori eradication
timeFrame: 10 days - 14 days
Secondary outcomes:
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Army Hospital
Study officials:
References:
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