Linaclotide effective even in severe IBS

Linaclotide is safe and effective, even in severe cases of irritable bowel syndrome with constipation, according to a post-hoc analysis of phase III trial data.

Indeed, more acute patients "responded ... just as well as, if not better than, the intent-to-treat population, which included patients with milder abdominal symptoms," wrote Dr. Satish S. C. Rao and colleagues in the April issue of Clinical Gastroenterology and Hepatology (doi:10.1053/j.gastro.2014.01.0130).

According to Dr. Rao of Georgia Regents University, Augusta, although the guanylate cyclase-C agonist is already Food and Drug Administration approved for irritable bowel syndrome–constipation (IBS-C) subtype in 2012, it has not been explicitly tested in patients with more severe disease.

In the current study, Dr. Rao and his fellow investigators looked specifically at several symptoms common to this population: pain, cramping, bloating, fullness, and discomfort.

Patients who ranked at least one of these as being greater than or equal to 7 at baseline were scored as severe, where 0 represents no symptoms and 10 represents the worst possible symptoms.

Overall, out of a total intent-to-treat population of 1,602 patients, 376 reported severe pain, 507 reported severe discomfort, 702 reported severe bloating, 708 reported severe fullness, and 359 reported severe cramping.

Given the overlap between the pain/cramping and bloating/fullness cohorts, the investigators organized the severe IBS group into four subgroups: patients reporting severe pain as their primary complaint (including cramping), severe bloating (including fullness), severe discomfort, and those patients who reported severe symptoms in all three realms.

Demographics were similar between each subgroup and in the overall study population, "although the subpopulations tended to be younger, more female, and more non-white than the intent-to-treat population," the investigators wrote.

Patients were randomized to receive placebo or linaclotide 290 mcg once daily; primary endpoints for this study were assessed at 12 weeks.

The investigators found that, among all severe IBS patients in all subgroups, the mean changes from baseline were significantly greater for linaclotide-treated patients compared with placebo patients for pain, discomfort, bloating, fullness, and cramping (P less than .0001 for all).

Looking at the whole severe IBS cohort, the authors found that 59%-61% of linaclotide patients reported adequate relief of IBS symptoms at week 12, compared with 28%-32% of placebo patients (P less than .0001).

Of those with severe IBS, 70%-77% of linaclotide-treated patients reported being "moderately, quite, or very satisfied" with treatment at week 12, but only 41%-43% of placebo-treated patients said the same (P less than .0001).

Finally, looking specifically at severe versus more mild IBS cases, the investigators found that, overall, the severe IBS cohort reported significantly greater improvements with the drug, compared with their less severe, drug-treated counterparts in the intent-to-treat population.

The most common side effect – diarrhea – occurred in almost one-fifth of linaclotide-treated patients with severe IBS, versus an occurrence rate of 1.6%-2.1% among placebo-treated patients.

In addition to the finding that linaclotide is effective in severe IBS-C, the investigators also wrote that their finding of severe bloating and fullness in many of these patients should give clinicians pause.

"Pain or discomfort is considered a clinical hallmark of IBS," they wrote, but "the presence of bloating and fullness in patients with IBS-C may warrant greater attention in clinical practice as well as in clinical trial design."

Several of the investigators are employees of Ironwood Pharmaceuticals, maker of linaclotide. Additionally, Dr. Rao and another investigator disclosed financial relationships with the pharmaceutical company, which also funded the study.