A substantial proportion of patients treated with linaclotide for irritable bowel syndrome with constipation (IBS-C) experience a delayed response, an industry-funded analysis of four randomized trials found.
Researchers pooled time-to-response data from one phase 2b and three phase 3 randomized controlled trials conducted at centers across the U.S. and Canada among patients who met Rome II or Rome III criteria for IBS-C and had a baseline abdominal pain severity score of 3 or more. Only data from patients who received the immediate-release dose of 290 µg of linaclotide or placebo within the first 12 weeks of the treatment period from each trial were included. The researchers analyzed response time for abdominal symptoms and complete spontaneous bowel movements (CSBMs) after linaclotide use. Per FDA recommendations, they defined response as an improvement of 30% or more from baseline in the weekly average scores for abdominal pain, discomfort, and bloating, and an increase of one or more CSBMs per week from baseline and achievement of three or more per week. They categorized patients as early responders (four weeks or less), late responders (between four and 12 weeks), or nonresponders. Results were published Nov. 16 by the American Journal of Gastroenterology.
Among 2,350 patients with IBS-C, 1,172 received placebo and 1,178 received linaclotide. For linaclotide-treated patients, the median time to response was three weeks for abdominal pain and discomfort and four weeks for bloating, compared with six, seven, and eight weeks, respectively, for placebo. Each time-to-response curve showed a significant separation between linaclotide and placebo (P<0.0001). While more than 50% of linaclotide-treated patients had early response in their abdominal symptoms, a substantial proportion were late responders for abdominal pain (15%), discomfort (15%), or bloating (17%). The median time to an increase of one or more CSBMs per week from baseline was two weeks in patients who received linaclotide versus four weeks for those who received placebo. The median time to achieve three or more CSBMs per week was four weeks for linaclotide-treated patients; those who received placebo did not reach this goal during the 12-week treatment period (curve separation, P<0.0001). Overall, 8.5% of patients were late responders to linaclotide using the threshold of an increase of one or more CSBMs per week from baseline, while 10.9% were late responders using the criterion of achieving three or more CSBMs per week.
The study population may not be representative of the real-world IBS-C population because of the stringent definitions used to enroll patients, among other limitations, the authors noted. They added that these results can help clinicians and patients set expectations on how long it may take to respond to linaclotide, potentially reducing the likelihood of premature discontinuation of treatment.
“Time to response differs for individual symptoms, and individual patient characteristics may influence this,” the authors wrote. “A lack of improvement in one symptom does not negate the possibility of a response for others, highlighting how important it is that clinicians review any benefit across all symptoms with patients and do not assume treatment futility at 4 weeks.”