286 Efficacy and Safety of Once Daily Linaclotide Administered Orally for 12-Weeks in Patients With Chronic Constipation: Results From 2 Randomized, Double-Blind, Placebo-Controlled Phase 3 Trials

Core Aspects of Clinical Development and Trials in Chronic Idiopathic Constipation

“…This compares to treatment responses of 30% to 40% using SBM-based definitions, but with higher placebo responses and overall lower levels of statistical significance (Camilleri et al, 2008;Lembo et al, 2010a;Quigley et al, 2009;). The observation that only a quarter of patients normalize bowel function with monotherapy-based trials suggests that the majority of patients will require combination therapy with these agents in the clinic.…”

“…Irrespective of these considerations, all compounds for the treatment of constipation possess the inherent potential to produce diarrhea when administered at sufficient doses, due presumably to their exaggerated pharmacology rather than some off-target activity. Diarrhea led to study discontinuation in almost 5% of subjects in recent Phase 3 trials of linaclotide (Lembo et al, 2010a).…”

“…Furthermore, its binding to GCC receptors is pH-dependent. Perhaps as a result of these properties, plecanatide manifests three-fold to five-fold lower potency compared with linaclotide in human studies on a concentration basis (Lembo et al, 2010a;Shailubhai et al, 2010). Plecanatide was associated with a lower incidence of diarrhea in a preliminary trial of constipated patients, but this could potentially be representative of lower rates of intestinal secretion induced by the compound (Shailubhai et al, 2010).…”

“…Three CSBM per week, i.e., approximately one BM every other day, represents normalization of bowel function in many individuals (Drossman et al, 1982), and therefore has clinical meaningfulness. The linaclotide Phase 3 program provided for coprimary endpoints that included achieving both ≥ 3 CSBM and improvement of ≥ 1 CSBM/week (Lembo et al, 2010a). The achievement of ≥ 3 CSBM per week is a more stringent and clinically more relevant endpoint than improvement of ≥ 1 CSBM, and efficacy responses on this co-primary endpoint predominantly reflect the subject's response on the first co-primary.…”

“…Use of rescue medications and time to first bowel movement have also served as secondary or exploratory endpoints in selected trials. Sponsors have typically included global endpoints such as www.intechopen.com constipation severity and adequate relief as secondary or exploratory endpoints (Lembo et al, 2010a), and the FDA supports use of these outcomes other than for primary efficacy endpoints (US Food and Drug Administration, 2009).…”