Clarithromycin, Amoxicillin, and Metronidazole Based Regimens to Treat Helicobacter Pylori Infections in Colombia
Condition: Helicobacter Pylori Infection
MeSH terms: Infections; Communicable Diseases; Helicobacter Infections
Study type: Interventional
Phase: Phase 3

Summary: 
      More than half of the world's population is infected with Helicobacter pylori, a bacterium
      that colonizes the human stomach. Although most infected subjects live free of symptoms and
      disease outcomes (except superficial gastritis), only a few develop peptic ulcers or gastric
      cancer, while some others may develop non-ulcer dyspepsia. Current clinical practice for the
      management of peptic ulcer disease includes testing for and treating H. pylori, if present.
      Although there are triple therapies that contain 2 antibiotics plus a bismuth compound, a
      proton-pump inhibitor, or a H2-receptor antagonist which are effective at eliminating H.
      pylori in Europe and North America, these treatments are dramatically less effective in
      developing countries. Our recent meta-analysis showed quadruple therapies containing
      clarithromycin, amoxicillin, metronidazole and a proton pump inhibitor to be effective in the
      presence of clarithromycin or metronidazole resistance. However, this regimen has yet to be
      tested in a developing country. Therefore, in the current randomized clinical trial in Pasto,
      Colombia, we aim to examine the effectiveness of clarithromycin, amoxicillin, metronidazole
      with and without a proton pump inhibitor compared to the Food and Drug Administration
      approved 10-day regimen containing clarithromycin, amoxicillin and omeprazole. Since
      antibiotic therapy is most effective within a specific gastric pH range, and since mutifocal
      atrophy results in damage and loss of the acid producing parietal cells, we will test the
      efficacy of our modified therapy stratified by diagnosis of multifocal atrophic gastritis.
    

Detailed description: 
      Warren and Marshall's Noble prize winning discovery of Helicobacter pylori, and their
      subsequent work which showed that gastritis and peptic ulcers could be successfully treated
      by eradicating this bacterium, ultimately revolutionized how physicians treat peptic ulcer
      disease. However, our previous research has shown most treatments for H. pylori are
      dramatically less effective in the presence of drug resistance, especially in developing
      countries, where H. pylori is highly prevalent. Our recent meta-analysis, which prompted the
      Canadian Helicobacter Consensus Group to change their treatment guidelines for Canada, showed
      quadruple therapies of clarithromycin, amoxicillin, metronidazole (CAM) and a proton pump
      inhibitor to be effective in the presence of clarithromycin or metronidazole resistance.
      However, this regimen has yet to be tested in a developing country.

      Since Warren and Marshall's discovery, H pylori has also been implicated as a risk factor for
      gastric cancer and possibly non-ulcer dyspepsia (NUD), while conflicting evidence suggests it
      may be a protective factor for disease outcomes of the esophagus. Glandular atrophy caused by
      H. pylori is believed to initiate the precancerous process by disrupting the mucus barrier,
      allowing carcinogens direct contact to gastric cells. Atrophy is followed by an increase in
      pH in the gastric cavity. Carcinogens, epithelium mutations, rapid cell turnover, toxins, and
      virulence factors such as H. pylori strains containing CagA and vacuolating cytotoxin (VacA)
      proteins, and the cagA and vacA genes that encode for these proteins, are putative risk
      factors for progression to intestinal metaplasia, followed by dysplasia, and then invasive
      carcinoma.

      Much debate exists about whether anti H. pylori treatments benefit infected subjects with
      non-ulcer dyspepsia. A meta-analysis of short-term trials suggest that H. pylori is a weak
      risk factor for dyspepsia in some unidentified populations. This information together with a
      cost-effectiveness analysis resulted in the European Maastricht 2-2000 Consensus
      recommendation that young patients with persistent dyspepsia be tested and, if infected,
      treated for H. pylori ('the test-and-treat strategy'). Nevertheless, without strong evidence
      supporting this strategy for dyspepsia, and devoid of an understanding of how H. pylori
      elimination affects symptoms, this strategy has not gained wide spread acceptance and it is
      not part of the current standard of care in many countries. However, studies which examine
      the effect of H. pylori on symptoms in developing countries, where most infections occur, are
      lacking.

      Although gastric cancer rates have declined in developed countries, higher rates have been
      observed in minority and immigrant groups, and it is still the 2nd most frequent cancer
      worldwide. In Nariño, Colombia, the incidence for gastric cancer is estimated to be the
      highest in the world with a rate up to 150/100,000/yr. In 1993-94 we conducted a randomized
      clinical trial aimed at short-term reduction of inflammation and epithelial damage in the
      stomachs of H. pylori infected subjects with NUD from the general population of Pasto, the
      capital of Nariño (the "Pasto cohort"). Data from this trial and our subsequent meta-analysis
      showed that classical anti-H. pylori treatments which effectively eliminate H. pylori in
      Europe and North America, were not effective in populations such as Pasto which has a high
      prevalence of the infection and a high prevalence of metronidazole resistance.

      We will test the efficacy of promising 14-day clarithromycin-, amoxicillin- and
      metronidazole-(CAM) triple and quadruple based regimens for eradication compared with the FDA
      recommended 10-day regimen (clarithromycin, amoxicillin, and omeprazole). Since antibiotic
      therapy is most effective within a specific gastric pH range, and since mutifocal atrophy
      results in damage and loss of the acid producing parietal cells, we will test the efficacy of
      our modified therapy stratified by diagnosis of multifocal atrophic gastritis. We hypothesize
      that: 1) among H. pylori infected subjects in the Pasto cohort with multifocal atrophic
      gastritis, those who are randomized to a 14-day triple therapy with CAM will more likely
      eradicate their H. pylori infection compared with those randomized to the FDA approved
      regimen; 2) among H. pylori infected subjects in the Pasto cohort without multifocal atrophic
      gastritis, those who are randomized to a 14-day quadruple therapy of CAM plus omeprazole,
      will be more likely eradicate their H. pylori infection compared with those randomized to the
      FDA approved regimen; and 3) among H. pylori infected subjects in Pasto without a previous
      histological diagnosis, those randomized to a 14-day CAM therapy will be more likely to
      eradicate H. pylori compared with those randomized to the FDA approved regimen. Therefore,
      our primary aim is to conduct a randomized clinical trial in Pasto, Colombia to assess the
      diagnosis-specific efficacy of a 14-day CAM triple therapy, and a 14-day clarithromycin,
      amoxicillin, metronidazole and omeprazole quadruple therapy to eliminate H. pylori compared
      with the FDA approved 10-day clarithromycin, amoxicillin, and omeprazole triple therapy in
      subjects who have never been treated for H pylori infection.
    

Intervention name(s): Clarithromycin, Metronidazole, Amoxicillin (+Omeprazole); Clarithromycin, Amoxicillin, Omeprazole
Intervention type(s): Drug; Drug
Intervention description(s): Clarithromycin 500 mg bid, metronidazole 500 mg tid, and amoxicillin 500mg tid with or without omeprazole 20 mg bid for 14 days; Clarithromycin 500 mg bid, amoxicillin 1 g bid, and omeprazole 20 mg bid for 10 days
Other intervention name(s): Biaxin, Flagyl, Amoxil, Prilosec; Biaxin, Amoxil, Prilosec
Intervention MeSH terms: Amoxicillin; Metronidazole; Clarithromycin; Omeprazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Randomized clinical trial; Helicobacter pylori; clarithromycin; metronidazole; amoxicillin; proton pump inhibitor; Colombia