Trial Information

A Randomized Clinical Trial to Examine the Efficacy of a Clarithromycin-, Amoxicillin-, and Metronidazole-Based Regimen to Eradicate Helicobacter Pylori Infections in Pasto, Colombia

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.