"An antibiotic currently indicated for hepatic encephalopathy and traveler's diarrhea has shown promise in the treatment of Crohn's disease (CD).
RETIC-03, a large phase 2 trial presented at the 18th Annual United European Gastroenterology Week in Barcelona, Spain, showed that rifaximin-EIR (extended intestinal release) was able to achieve clinical remission of Crohn's sequelae in up to 62% of patients out to 12 weeks, according to study investigator, Herbert Lochs, MD, from the Medical University in Innsbruck, Austria.
RETIC-03, a multicenter, multinational, randomized, double-blind, placebo-controlled study, was a comparison of 3 twice-daily doses of rifaximin-EIR (400 mg, 800 mg, and 1200 mg) and placebo in a cohort of 402 patients with active CD. The study's primary end point was remission of CD at 12-week follow-up.
Results showed that at 12 weeks, all active treatment groups achieved remission more often than placebo (P < .04), with the highest rate (62.2%) observed for the 800 mg regimen.
Response to treatment was initially dose-dependent, rising from the 400 mg to the 800 mg threshold. However, the highest dose (1200 mg) produced the least efficacy (47.5%) among the active treatment group, and the highest rate of discontinuations. Reasons for this are unclear, said Dr. Lochs. "The main adverse events tended to be mild, and the majority were gut-related, as in pain, vomiting, and diarrhea — which, frankly, are very difficult to separate out from the symptoms of Crohn's itself."
Commenting on his motivation for conducting RETIC-03, Dr. Lochs said that he was trying to move away from CD treatment methods that rely on suppression of the patient's immune system. "It's not something you ideally want to do — not in the long term."
In the current hypothesis for the pathogenesis of CD, he explained, there is a change in the intestinal microbiota, whereby pathogenic bacteria disrupt the gut's mucosa, which activates the immune system. Rather than inhibit the immune response, Dr. Lochs wants to attenuate the reasons for its activation.
The choice of rifaximin was based on case reports of its potential utility in CD, and the fact that it is specific to the gut. "The formulation stays in the lumen; there's no systemic effect that might lead to overall antibiotic resistance," said Dr. Lochs. In theory, this should lead to fewer adverse events than other antibiotics, he added.
"We need to do a confirmatory study, of course, but this study has shown 2 things that are different and important. First, it was possible to initiate remission with an antibiotic in active Crohn's disease, and second, this remission could be maintained." Dr. Lochs said that future studies (as yet unplanned) would address long-term maintenance of remission.
If it's so simple, why haven't we tried it before?
"The data for antibiotics [in CD] are out there, and the science makes sense," said Sunanda Kane, MD, from the Mayo Clinic in Rochester, Minnesota, and chair of the Patient Education Committee of the Crohn's and Colitis Foundation. "The problem up to now has been that no company has wanted to fund a large enough trial with the appropriate antibiotic."
Dr. Kane said that there is perhaps a different sort of motivation for such a study in the European Union, pointing out that the biologics commonly used in CD are very expensive and often not covered; in some countries, they are not even approved.
"What they are trying to do is to find an alternative to biologics that may be safer and work just as well," she observed.
Dr. Kane finds the choice of rifaximin in this study to be both prudent and just a bit ironic. "There are case studies that show efficacy, and the fact that it's so [gastrointestinal]-specific, so targeted, is great, but rifaximin is not a cheap antibiotic." Still, she admitted, the price is nowhere near that of a biologic, nor does it carry the same potential for serious adverse effects."
18th Annual United European Gastroenterology Week: Abstract 3075. Presented October 26, 2010.
RETIC-03, a large phase 2 trial presented at the 18th Annual United European Gastroenterology Week in Barcelona, Spain, showed that rifaximin-EIR (extended intestinal release) was able to achieve clinical remission of Crohn's sequelae in up to 62% of patients out to 12 weeks, according to study investigator, Herbert Lochs, MD, from the Medical University in Innsbruck, Austria.
RETIC-03, a multicenter, multinational, randomized, double-blind, placebo-controlled study, was a comparison of 3 twice-daily doses of rifaximin-EIR (400 mg, 800 mg, and 1200 mg) and placebo in a cohort of 402 patients with active CD. The study's primary end point was remission of CD at 12-week follow-up.
Results showed that at 12 weeks, all active treatment groups achieved remission more often than placebo (P < .04), with the highest rate (62.2%) observed for the 800 mg regimen.
Response to treatment was initially dose-dependent, rising from the 400 mg to the 800 mg threshold. However, the highest dose (1200 mg) produced the least efficacy (47.5%) among the active treatment group, and the highest rate of discontinuations. Reasons for this are unclear, said Dr. Lochs. "The main adverse events tended to be mild, and the majority were gut-related, as in pain, vomiting, and diarrhea — which, frankly, are very difficult to separate out from the symptoms of Crohn's itself."
Commenting on his motivation for conducting RETIC-03, Dr. Lochs said that he was trying to move away from CD treatment methods that rely on suppression of the patient's immune system. "It's not something you ideally want to do — not in the long term."
In the current hypothesis for the pathogenesis of CD, he explained, there is a change in the intestinal microbiota, whereby pathogenic bacteria disrupt the gut's mucosa, which activates the immune system. Rather than inhibit the immune response, Dr. Lochs wants to attenuate the reasons for its activation.
The choice of rifaximin was based on case reports of its potential utility in CD, and the fact that it is specific to the gut. "The formulation stays in the lumen; there's no systemic effect that might lead to overall antibiotic resistance," said Dr. Lochs. In theory, this should lead to fewer adverse events than other antibiotics, he added.
"We need to do a confirmatory study, of course, but this study has shown 2 things that are different and important. First, it was possible to initiate remission with an antibiotic in active Crohn's disease, and second, this remission could be maintained." Dr. Lochs said that future studies (as yet unplanned) would address long-term maintenance of remission.
If it's so simple, why haven't we tried it before?
"The data for antibiotics [in CD] are out there, and the science makes sense," said Sunanda Kane, MD, from the Mayo Clinic in Rochester, Minnesota, and chair of the Patient Education Committee of the Crohn's and Colitis Foundation. "The problem up to now has been that no company has wanted to fund a large enough trial with the appropriate antibiotic."
Dr. Kane said that there is perhaps a different sort of motivation for such a study in the European Union, pointing out that the biologics commonly used in CD are very expensive and often not covered; in some countries, they are not even approved.
"What they are trying to do is to find an alternative to biologics that may be safer and work just as well," she observed.
Dr. Kane finds the choice of rifaximin in this study to be both prudent and just a bit ironic. "There are case studies that show efficacy, and the fact that it's so [gastrointestinal]-specific, so targeted, is great, but rifaximin is not a cheap antibiotic." Still, she admitted, the price is nowhere near that of a biologic, nor does it carry the same potential for serious adverse effects."
18th Annual United European Gastroenterology Week: Abstract 3075. Presented October 26, 2010.
