Repeat rifaximin treatment yields symptom improvements in IBS-D patients who relapse
Repeat 2-week rifaximin treatment course (up to three) appears to be effective and safe for patients with relapsing symptoms of diarrhoea-predominant irritable bowel syndrome (IBS-D), producing marked improvements in abdominal pain and frequency of loose stools without increasing the incidence of adverse events, according to the results of a phase III trial.
The primary endpoint of percentage of responders during the 4-week follow-up after the first repeat treatment course was greater with rifaximin than with placebo (worst case analysis: 38.1 vs 31.5 percent; Δ 7 percent; p=0.03; sensitivity analysis: 40.2 vs 32.4 percent; Δ 8 percent; p=0.01). Responders were defined as patients who simultaneously had a ≥30-percent reduction from baseline in abdominal pain and ≥50-percent reduction from baseline in frequency of loose stools for at least 2 weeks within the 4-week period. [Gastroenterology 2016; 151:1113–1121]
Specifically, there was a significant difference in the percentage of responders for abdominal pain, in favour of rifaximin (50.6 vs 42.2 percent; Δ 9 percent; p=0.018). On the other hand, there was no significant between-group difference in the response for stool consistency (51.8 vs 50 percent; Δ 2 percent; p=0.42).
Rifaximin was also associated with significantly greater improvements in recurrence prevention (13.2 vs 7.1 percent; p=0.007) and durable response (17.1 vs 11.7; p=0.04), but not bloating (46.6 vs 41.2 percent; p=0.14).
Treatment-related adverse events occurred in 1.8 and 2.6 percent of patients in the rifaximin and placebo arms, respectively. Events leading to study withdrawal were rare and reported only in 1 patient in each treatment arm. Increased alanine aminotransferase levels and nausea were the most commonly reported adverse events.
The trial involved adult patients with IBS-D (mean abdominal pain and bloating scores of ≥3, and loose stool) who had previously responded to a 2-week course of open-label rifaximin. A total of 636 patients who relapsed during an observation period of 18 weeks were randomized to receive repeat treatment with rifaximin (500 mg three times daily; n=328; mean age 47.9 years) or placebo (n=308; mean age 45.6 years).
“A potential explanation for the relatively small delta (∼Δ 7 percent) observed after repeat treatment with rifaximin or placebo is that patients who had recurrent IBS symptoms after responding to open-label rifaximin reported that the severity of these symptoms was substantially lower than at open-label baseline,” researchers explained.
They added that the lesser symptom severity at the onset of the first repeat treatment course played a role in the reduction of the statistical power to detect measurable improvement in symptoms, which was attributable to a floor effect.
Despite the positive outcome of the trial, the potential risk-benefit profile of repeat administration of nonsystemic antibiotics after three courses of treatment still remains unclear, especially with regards to IBS-D patients who might require long-term symptom management.
Understanding the treatment algorithm in patients who may lose responsiveness to rifaximin warrants additional research, researchers said.
Pain reductions not translatable to patient satisfaction
Dr Gwee Kok Ann, FAMS, FRCP, an adjunct associate professor of medicine at the National University of Singapore’s Yong Loo Lin School of Medicine and who was not involved in the study told MIMS that many IBS patients were being treated with prolonged courses of antispasmodic, probiotic and antidiarrheal treatment. This is in the context of the presumption in the current treatment paradigm that IBS is chronic.
“And yet, experience with rifaximin points to a possible symptom-free interval of about 3 months after just a single two-week course of treatment. If a repeat two-week course can induce another 3 months’ remission, this will be appealing in terms of medication-free periods and cost savings,” Dr Gwee said.
However, he questioned whether the defined endpoints for reductions in abdominal pain in the present study were meaningful. “The Rome criteria prioritises abdominal pain as the mandatory symptom. Therefore, a reduction of just over 30 percent may not translate into satisfaction for the patient.”
“I would have liked to see an evaluation of patient satisfaction in this trial. Furthermore, it is important to know whether the symptom improvement was sustained beyond 2 weeks, and by how long. Therefore, for me the more clinically meaningful endpoint would have been the secondary endpoint of preventing recurrence during the 10 weeks following completion of treatment,” Dr Gwee said.
Furthermore, he pointed out the study did not evaluate the psychological profile of the study population, in addition to the lack of information regarding the type of treatment facilities from which they were recruited.
“For example, if subjects were recruited from tertiary care centres, or from centres with interest in psychosomatic medicine, we can expect an enrichment with patients who have psychological disturbances, which are poor prognostic markers,” he said.
Dr Gwee added that studies such as the current one and those documenting a role for immune activation and gut dysbiosis underscored the need to move away from the idea that IBS is just a psychological problem.
“Clinicians should update their knowledge of the various pathophysiology of IBS that may be quite effectively targeted with specific treatment. [They] should not dismiss their patients as neurotic, and should not depress their patients by telling them that there is no hope.”