Concomitant Versus Hybrid Regimen for H. Pylori Eradication
Condition: H.Pylori Infection; H.Pylori Gastrointestinal Disease; H. Pylori Associated Phlegmonous Gastritis
MeSH terms: Gastritis; Gastrointestinal Diseases; Digestive System Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      10 day concomitant versus 14 day hybrid regimen as first line H. pylori eradication treatment
      in a high clarithromycin resistance area. A multicenter, randomized, equivalence trial.
    

Detailed description: 
      RESEARCH PROTOCOL:

      TITLE "10 day concomitant versus 14 day hybrid regimen as first line H. pylori eradication
      treatment in a high clarithromycin resistance area. A multicenter, randomized, equivalence
      trial."

      INTRODUCTION

      Helicobacter pylori (H. pylori) is a global human pathogen implicated in the pathogenesis of
      prevalent and serious diseases mainly peptic ulcer disease and gastric malignancy.1 Recent
      guidelines propose H. pylori eradication every time that it is found with the usual detection
      methods.2 Successful eradication largely depends on the choice of antibiotics in which the
      microbe is mostly sensitive.3 Usual first line therapies contained a proton pump inhibitor
      (PPI) and two antibiotics, clarithromycin with amoxicillin or metronidazole when amoxicillin
      wasn't indicated.4 Eradication rates have been initially acceptable reaching over 80% in per
      protocol analyses.5,6 However in late years H. pylori has developed an increasingly high
      resistance profile which has reached over 20% in most European countries, including ours. As
      a consequence, eradication rates with triple regimens declined to percentages less than 80%
      in per protocol analyses.7-9 Currently acceptable schemes include the already known bismouth
      containing quadruple regimen and the non bismouth quadruples namely concomitant, sequential
      and hybrid.10,11 In our country the 10 days concomitant regimen presents stable and high
      eradication rates which are significantly better than the standard triple and sequential
      regimens of the same duration.12-14 In two recent studies concomitant had a significant
      advantage over sequential on metronidazole resistant strains as well as on dual resistant to
      both clarithromycin and metronidazole strains.14,15 The hybrid regimen is the less studied
      first line regimen in Europe.16 In a recent study, on a Greek population, a 14 days hybrid
      regimen achieved encouraging results and the only predictive factor for failure has been dual
      resistance.17 To date there hasn't been any comparative study between 10 days concomitant and
      14 days hybrid regimens.16

      PURPOSE OF STUDY The investigators designed an equivalence trial between the 10 days
      concomitant and 14 days hybrid regimens in a Greek population.The investigators primary
      outcome is to compare total eradication rates between these two regimens in intention to
      treat and per protocol analyses. Secondary outcomes are to compare eradication rates in
      respect to genotypic and phenotypic resistance profiles, the effect of antibiotic resistance
      on therapy, patient's compliance, adverse events and economic evaluation of the two regimens.

      PATIENTS - METHODS

      Patient selection Patients of 18 years or older with dyspepsia / or iron deficiency anaemia,
      referring for upper GI endoscopy and found to be infected with H. pylori (positive rapid
      urease test), naïve to H. pylori eradication treatment, will be invited to participate in the
      study. Exclusion criteria are: age below 18 years, presence of severe co-morbidities (i.e.
      liver cirrhosis, renal failure, haematological, neurological, psychiatric, cardiovascular or
      pulmonary disease), previous gastric surgery, gastric malignancies, Zollinger-Elisson
      syndrome, known allergy or other contraindications to the study medications, previous H.
      pylori treatment, use of antibiotics , bismuth salts , NSAIDS or aspirin in the preceding
      month, use of PPI in the preceding two weeks and not willing to participate in the study.
      Pregnant or lactating women will also be excluded.

      Study Design The study will be prospective. Upper GI endoscopy including two antral biopsies
      for rapid urease test (CLO-test) will be performed at each patient. In patients tested
      positive two additional specimens (from the antrum and corpus) will be sent to a reference
      laboratory for culture and antibiotic susceptibility tests. In cases with indication for
      histology or equivocal CLO-test results, at least two specimens will be taken from the antrum
      and corpus respectively, to confirm H. pylori gastritis using haematoxylin-eosin and modified
      Giemsa staining. In equivocal cases an immunohistochemical method can be used. Patients
      tested positive by urease test and/or histology will be allocated to either treatment group.
      Every patient will sign an informed consent in order to participate in the study.
      Additionally, a careful medical history will be obtained and complete clinical examination
      performed (including appropriate blood or other tests if indicated) prior to inclusion into
      the study.

      Participants will be randomly assigned, in a 1:1 basis, to one of two treatment groups namely
      concomitant and hybrid. Randomization will be organized centrally by an independent assistant
      investigator using a computer-generated randomization method, using a block size of four.
      This will produce a separate number for each patient sealed in an opaque envelope and kept in
      his office throughout the study. After obtaining informed consent, the investigators would
      call the research assistant to open the envelope for the allocated regimen. All data will be
      inserted in a computer database and elaborated by the participating investigators. The trial
      is not blinded for patients and recruiting physicians, regarding treatment regimen, as in
      most randomized controlled H. pylori eradication trials.

      Interventions

      After the confirmation of H. pylori infection, eligible patients randomly assigned to either
      concomitant or hybrid treatment group will receive:

        -  Concomitant for 10 days, including 40 mg of esomeprazole bid, amoxicillin 1g bid,
           clarithromycin 500mg bid and metronidazole 500mg bid.

        -  Or Hybrid for 14 days, including 40 mg of esomeprazole bid and amoxicillin 1g bid, for
           the first 7 days followed by esomeprazole 40mg bid, amoxicillin 1g bid, clarithromycin
           500mg bid and metronidazole 500mg bid, for another 7 days.

      Esomeprazole will be given before and antibiotics after meals, in both regimens. In the
      post-treatment period, symptomatic patients will be allowed to use antacids on demand.
      Antibiotics or other medications interfering with the treatment results will be prohibited
      during the study period. Efficacy of treatment will be evaluated 4-6 weeks after completion
      of antibiotic therapy by 13C-urea breath test (13C-UBT) performed according to the standard
      European protocol. In patients requiring a follow-up endoscopy due to peptic ulcer disease,
      persisting or recurring symptoms, the diagnostic test of choice will be histological
      examination of four samples taken, in pairs, from the antrum and from the corpus and stained
      by modified Giemsa.

      Tolerability and adherence Side effects of treatment will be assessed on a structured
      clinical interview with a specific questionnaire completed immediately after the end of
      eradication therapy and at the final re-evaluation. During the interview, patients will be
      asked to grade the severity of each adverse event experienced as "mild" (transient and well
      tolerated), "moderate" (causing discomfort and partially interfering with common everyday
      activities), or "severe" (causing considerable interference with patients' daily
      activities).18 Incapacitating or life-threatening complications will be classified as serious
      and will be reported to regulatory agency (National Organization of Medicines). Adherence to
      treatment will be assessed by providing all patients with a pre-structured printed table with
      all dosages illustrated, asking to tick each time a pill was consumed and bring it back along
      with any tablet not consumed, for pill counting. In case of discrepancies found between the
      structured printed table and residual medication, the latter will be taken into account to
      evaluate patient's adherence. Poor adherence is defined as <90% of the total medication
      taken.

      Culture and antibiotic susceptibility tests Isolation of clinical H. pylori strains H. pylori
      clinical strains will be isolated from gastric biopsies. All biopsies will be placed in
      thioglycollate medium (Oxoid, Basingstoke, UK) and will be sent to the Laboratory of Medical
      Microbiology (Hellenic Pasteur Institute) for H. pylori isolation within 2-4 hours after
      endoscopy. Following addition of sterile glass beads, biopsy samples will be vigorously
      vortexed and 100μl of homogenate will be cultured for up to 7 days, at 37°C under
      microaerophilic conditions (CampyPak-Plus, Becton-Dickinson, Cockeysville, MD), on Columbia
      agar plates containing antibiotics (vancomycin 10μg/mL, trimethoprim 10μg/mL, polymyxin B 104
      IU/L, amphotericin B 2μg/mL, nalidixic acid 10μg/mL, bacitracin 30μg/mL and fluorocytosine
      5μg/mL), supplemented with 8%v/v horse blood and 1% v/v Vitox (Oxoid, Basingstoke, UK).
      Culture sweeps, as well as individual colonies will be collected and frozen at -80°C, until
      used.

      Antibiotic susceptibility testing Antibiotic susceptibility testing of H. pylori will be
      performed utilizing E-test strips (BioMerieux, Marcy l'Étoile, France), according to the
      manufacturer's instructions, on Mueller Hinton agar medium (Beckton Dickinson) supplemented
      with 10% horse blood. Briefly, agar plates will be freshly prepared and used within 7 days
      following their preparation. Bacterial inoculum will be prepared from a 1 or 2 day old
      culture and bacterial suspension will be adjusted to McFarland 3 turbidity (approx. 108
      colony forming units-CFU/mL). E-test strips will be applied with sterile forceps to the dried
      agar surface, following application of the bacterial inoculum and plates will be incubated at
      37°C under microaerophilic conditions. Results will be read at 72 hours. MIC clinical
      breakpoints used to define resistance according to EUCAST will be: clarithromycin (>0.5
      mg/L), levofloxacin (>1 mg/L), tetracycline (>1 mg/L), metronidazole (>8 mg/L) and
      amoxicillin (>0.12 mg/L). To detect genotypic resistance to clarithromycin and levofloxacin a
      real time PCR will be implemented in cultured H. pylori strains.

      Sample size calculation The study is designed to prove or reject equivalence between the two
      eradication regimens under study namely 10 days concomitant and 14 days hybrid (equivalence
      trial). Based on the results of previous studies eradication rates over 85% in intention to
      treat and over 90% in per protocol analyses have been found for both regimens.17 According to
      international statistical rules (FDA) two regimens are considered equivalent when the
      confidence intervals of the difference between their eradication rates do not exceed 15%.
      Using the Monte Carlo (500 X 500 runs) simulation system and taken into account that in the
      existing Greek studies14-16 eradication rates for hybrid regimen are between 86 and 90% in
      intention to treat analysis we calculated a sample size of 150 patients in each treatment arm
      (with a 10% drop out rate) in order to get an 80% power in the study.

      Statistical analysis Comparisons of proportions will be done using the chi-square test.
      Continuous non-parametric data will be compared using the t test. Stepwise multivariate
      logistic regression analysis will be performed to evaluate factors influencing H. pylori
      eradication in patients who had a final treatment outcome with either concomitant or hybrid
      therapy.
    

Intervention name(s): 10 day concomitant regimen; 14 day hybrid regimen
Intervention type(s): Drug; Drug
Intervention description(s): 10 Day Concomitant Hp therapy Concomitant for 10 days, including 40 mg of esomeprazole bid, amoxicillin 1g bid, clarithromycin 500mg bid and metronidazole 500mg bid; 14 Day Hybrid Hp therapy Hybrid for 14 days, including 40 mg of esomeprazole bid and amoxicillin 1g bid, for the first 7 days followed by esomeprazole 40mg bid, amoxicillin 1g bid, clarithromycin 500mg bid and metronidazole 500mg bid, for another 7 days.
Other intervention name(s): Amoxicillin 1gr bid from day 1 to day 10; Clarithromycin 500mg bid from day 1 to day 10; Metronidazole 500mg bid from day 1 to day 10; Esomeprazole 40mg bid from day 1 to day 10; Amoxicillin 1gr bid from day 1 to day to day 14; Clarithromycin 500mg bid from day 8 to day 14; Metronidazole 500mg bid from day 8 to day 14; Esomeprazole 40mg bidfrom day 1 to day to day 14
Intervention MeSH terms: Amoxicillin; Metronidazole; Clarithromycin; Esomeprazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: H. Pylori Infection; Gastritis; H.Pylori treatment; Treatment Resistance