Linaclotide reduces abdominal symptoms in constipation-predominant IBS

Use of linaclotide results in a significant reduction in several abdominal symptoms, such as bloating, discomfort, and pain, among patients with constipation-predominant irritable bowel syndrome (IBS-C) as compared with placebo, according to a study. In addition, reported adverse events (AEs) are in line with the established safety profile.

“This phase III-B trial using the novel Diary for IBS Symptoms-Constipation (DIBSS-C) Abdominal Score (AS) demonstrated the efficacy of linaclotide beyond the traditional symptoms of bowel movements and abdominal pain, with results indicating linaclotide can be used effectively as a single pharmacologic approach in the management of IBS-C-associated abdominal symptoms,” the researchers said.

A total of 614 patients with IBS-C (mean age 46.7 years, 81 percent female) were randomly assigned to receive linaclotide 290 μg or placebo daily for 12 weeks. AS was derived from the DIBSS-C and defined as the average of abdominal bloating, discomfort, and pain at their worst (0: none; 10: worst possible)

Overall change from baseline (CFB) was the primary endpoint, while CFB in 12-week AS evaluated using cumulative distribution function and 6-/12-week AS responder (AS improvement ≥2 points for ≥6-week/12-week) was secondary.

Linaclotide provided significant benefits across all prespecified endpoints relative to placebo. The mean overall CFB AS reduction was –1.9 for linaclotide and –1.2 for placebo (p<0.0001), while the 6-/12-week AS responder rate was 40.5 percent for linaclotide and 23.4 percent for placebo (odds ratio, 2.2, 95 percent confidence interval, 1.55–3.12; p<0.0001). [Am J Gastroenterol 2021;116:1929-1937]

Moreover, the most frequent treatment-emergent AE was diarrhoea, occurring in 4.6 percent of patients in the linaclotide arm and 1.6 percent in the placebo arm.

“The safety profile of linaclotide during this study was consistent with previous results, although the rate of diarrhoea was lower than that reported in previous linaclotide studies in IBS-C,” the researchers said. [Am J Gastroenterol 2012;107:1702-1712; Am J Gastroenterol 2012;107:1714-1724]

Psychometric analyses of clinical trial data established a 2.0-point change in the AS to be an appropriate threshold for identifying significant within-patient change. [Value Health 2020;23:362-369]

However, interaction with the US Food and Drug Administration (FDA) led to the selection of a threshold of 2.5 points, which was reflected in the linaclotide prescribing information, with a treatment difference of 15.5 percent (95 percent confidence interval, 8.6–22.3). [https://media.allergan.com/actavis/actavis/media/allergan-pdf-documents/product-prescribing/Final_labeling_text_10-2018-AR-updates-LINZESS-clean.pdf]

Of note, the IBS Working Group of the Critical Path Institute’s PRO Consortium developed the DIBSS-C, in cooperation with a patient advocacy organization, clinical experts, measurement experts, and input from the US FDA to support the construction of primary and secondary endpoints in IBS-C trials under the Drug Development Tool qualification program of the US FDA.

“To assess core abdominal symptoms important to patients with IBS-C, AS was derived from the three abdominal symptom items of the DIBSS-C (bloating, discomfort, and pain),” the researchers said.

“Psychometric analyses provide evidence of reliability, validity, responsiveness, and interpretability of the DIBSS-C AS for assessing treatment benefit in IBS-C clinical trials,” they added. [Value Health 2020;23:362-369]