Author(s): Jan Tack [*] 1
abdominal pain; bloating; constipation; European Medicines Agency; gender; irritable bowel syndrome; linaclotide; quality of life
Patients with irritable bowel syndrome (IBS) perceive symptoms of abdominal pain, bloating, constipation and fatigue as more important than other constipation-related symptoms such as straining, incomplete evacuation and hard stool consistency  . The fundamental clinical significance of these symptoms is reflected by both the EMA and the US FDA guidelines for the conduct of clinical trials in IBS, which recommend the assessment of abdominal pain as a key efficacy parameter  .
Linaclotide is a novel, first-in-class minimally absorbed guanylate cyclase C agonist recently approved by the EMA for the symptomatic treatment of moderate-to-severe IBS with constipation (IBS-C) in adults  , and by the FDA for the treatment of IBS-C and chronic constipation in adults [102,103] . Linaclotide acts locally on guanylate cyclase C receptors expressed in the intestine to stimulate secretion of chloride and bicarbonate ions and water into the intestinal lumen, improving gastrointestinal motility [3-5] . In animal models, activation of guanylate cyclase C receptors by linaclotide also results in desensitization of the nerves responsible for pain sensation in the bowel, alleviating visceral hypersensitivity and, therefore, symptoms of pain and discomfort  .
The potential for linaclotide as a novel therapy for IBS-C was demonstrated in early clinical trials. In Phase I studies in healthy volunteers, linaclotide was well tolerated with low oral bioavailability and a favorable safety profile [7,8] . Furthermore, linaclotide was shown to soften stool consistency and increase the frequency of bowel movements. Additional evidence of the beneficial effect of linaclotide on bowel symptoms of IBS-C was demonstrated in Phase II studies, where linaclotide accelerated colonic transit and emptying, and improved bowel function (including bowel movement frequency), stool consistency and severity of straining [9,10] . Linaclotide also significantly reduced abdominal pain severity associated with IBS-C  . Based on the balance of efficacy and tolerability, a dose of linaclotide 290 µg once daily was selected for Phase III evaluation. This article reviews the results of the Phase III studies, focusing on the EMA-specified end points.
Linaclotide for the treatment of IBS-C: evidence from Phase III studies
Both Study 31 and Study 302 were randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase III studies of linaclotide 290 µg [11-13] . Study 31 was a 12-week study with an additional double-blind, 4-week randomized-withdrawal period in which patients initially randomized to linaclotide were re-randomized (1:1) to linaclotide or placebo, and patients initially randomized to placebo were assigned to linaclotide  . Study 302 was a 26-week study with the primary end points evaluated over the first 12 weeks of treatment  .
In both studies, the coprimary end points prespecified by the EMA were 12-week abdominal pain or discomfort responders, and 12-week IBS degree-of-relief responders  ; these and other EMA-related end points are described in Table 1. Analysis of these studies using end points prespecified by the FDA has been described in detail elsewhere [11,13] .
Results from both studies showed that, in comparison with placebo, a significantly...