Pam Harrison

October 27, 2014

PHILADELPHIA — Rifaximin, a gut-targeted antibiotic for diarrhea-predominant irritable bowel syndrome, can be safely and effectively used to retreat patients who have relapsed after already being treated with the drug, report investigators.

These are the findings from the TARGET 3 trial presented here at the American College of Gastroenterology 2014 Annual Scientific Meeting. A second study of linaclotide, approved for constipation-predominant irritable bowel syndrome, was also presented at the meeting.

"Irritable bowel syndrome can lower a patient's quality of life and burden the healthcare system," said TARGET investigator Anthony Lembo, MD, from the Beth Israel Deaconess Medical Center in Boston. "Reliable symptom management may help patients return to a more normal lifestyle."

During the open-label phase of the Targeted, Nonsystemic Antibiotic Rifaximin Gut-Selective Evaluation of Treatment for Non-C IBS (TARGET 3) trial to assess repeat treatment with rifaximin, investigators evaluated 2579 patients.

Participants had diarrhea-predominant irritable bowel syndrome and received rifaximin 550 mg three times a day for 14 days; this was followed by a 4-week treatment-free period.

The composite end point, required for approval by the US Food and Drug Administration (FDA), was a decrease from baseline of at least 30% in mean abdominal pain score and a decrease from baseline of at least 50% in the number of days per week with a stool consistency of type 6 or 7.

Decrease in Abdominal Pain

The 42% of patients who met the composite end point were followed for an additional 18 weeks, and 36% of these did not experience symptom recurrence.

In fact, "approximately 72% of patients had improvement in at least one of the components of the composite end point," Dr Lembo pointed out.

The 636 patients who did not meet the composite end point and who experienced recurrent symptoms were randomized to receive retreatment with rifaximin 550 mg or placebo for 2 weeks, again followed by a 4-week treatment-free period.

Treatment response was better in patients treated with rifaximin than with placebo (33% vs 25%; P = .02).

However, these patients had lower symptom severity scores than they did at baseline. "This means that it was harder to show a difference between active treatment and placebo," Dr Lembo explained.

A second retreatment phase was followed by a 6-week treatment-free period. Again, treatment response was better in the rifaximin than in the placebo group (37% vs 29%; P = .04).

The key secondary end point of prevention of recurrence was better with rifaximin than placebo (13.2% v 7.1%; P = .0068), as was duration of response (17.1% vs 11.7%; P = .0419).

Adverse events were similar in the two groups.

In addition, "stool samples were taken from approximately 100 subjects selected at random," Dr Lembo explained. When a single course of rifaximin was compared with three courses, "there were no clinically relevant changes in bacterial sensitivity to other antibiotic classes, no emergence of pathogenic bacteria, no occurrence of opportunistic infections, and no alteration of the overall microbiota," he reported.

"The surprising part of this study was that about one-third of patients could go up to 22 weeks after receiving rifaximin and not have a relapse, so a good one-third of the people in this study who got the drug had a long-term benefit, which is better than we thought we'd get," Dr Lembo told Medscape Medical News.

"The part that was not surprising was that if you retreated patients with the drug, you saw effectiveness, compared with placebo," he noted.

"While we don't know if rifaximin will be approved by the FDA, we absolutely need more treatment options for diarrhea-predominant irritable bowel syndrome," he explained. "Right now, we only have one approved drug (alosetron). Patients and physicians have to enter into a prescription drug program if they use alosetron because of the side effects, and they are not always willing."

TARGET 3 was really designed to look at safety issues because the FDA had some concerns about retreating patients with diarrhea-predominant irritable bowel syndrome with the drug, said Brian Lacy, MD, from the Geisel School of Medicine, Dartmouth–Hitchcock Medical Center, in Lebanon, New Hampshire.

However, "36% of patients actually responded so well to upfront treatment that they did not continue on with the study, so upfront, there is actually a huge positive response to the drug," Dr Lacy told Medscape Medical News.

"If you look at the study very fairly using FDA composite end points, there was about a 10% therapeutic gain difference between rifaximin and placebo, with a number-needed-to treat of about 10 or 11, which is reasonable."

Linaclotide Study

In the long-term safety study of linaclotide, investigators showed that the agent continues to be well tolerated in patients with constipation-predominant irritable bowel syndrome, even if they experience diarrhea as an adverse effect of the drug.

"Most safety studies are confined, at most, to a year," said William Chey, MD, from the University of Michigan at Ann Arbor. "But with this study, we had a unique opportunity to follow a large number of patients on a new medication for an extended period of time. This allowed us to get a better handle on diarrhea as an adverse event in patients who remain on the drug."

The results presented by Dr Chey come from an 18-month safety study updating his team's original work (Am J Gastroenterol. 2012;107:1702-1712). In that 26-week study, the incidence of adverse events in patients with constipation-predominant irritable bowel syndrome was similar in the linaclotide and placebo groups, except for diarrhea, which led to more discontinuation in the linaclotide than in the placebo group (4.5% vs 0.2%).

During the 18-month safety follow-up, 32% of about 500 patients reported diarrhea at some point, almost all of which was mild to moderate.

More than three-quarters of patients who experienced diarrhea reduced their dose or temporarily discontinued the drug, and only 3% withdrew from the study because of diarrhea.

But levels of satisfaction in linaclotide-treated patients who reported diarrhea as an adverse event were similar to levels in patients who did not report diarrhea. "Although patients might have had some degree of diarrhea at some point during the course of the study, they obviously did not find it to be terribly disruptive or bothersome," he said.

"Diarrhea was self-reported; patients came back at set intervals and reported to the investigator whether they were having anything that they would consider an adverse event, so the information is probably not as granular as we would like," Dr Chey explained.

He added that linaclotide is best taken 30 to 60 minutes before a meal to achieve optimal effects.

The rifaximin study was funded by Salix Pharmaceuticals. The linaclotide study was funded by Ironwood Pharmaceuticals. Dr Lembo serves as a consultant for and is a member of the advisory board for Salix Pharmaceuticals. Dr Chey serves as a consultant for a number of pharmaceutical companies, including Ironwood Pharmaceuticals. Dr Lacy reports no relevant financial relationships.

American College of Gastroenterology (ACG) 2014 Annual Scientific Meeting: Abstract 45, presented October 21, 2014; and abstract 1111, presented October 20, 2014.


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