T1389 TD-5108, a Selective 5-HT4 Agonist, Is Consistently Better Than Placebo Regardless of Response Definition in Patients with Chronic Constipation

Abstract

TD-5108 is a highly selective, full agonist at the human 5-HT4 receptor. Multiple response definitions were pre-specified in a Phase 2 dose-ranging clinical trial of TD 5108 in patients (pts) with chronic idiopathic constipation (CIC). TD 5108 was consistently better than placebo in response rates across response definitions. Methods: This double blind, randomized, PBO controlled, parallel group, multicenter trial enrolled 401 adult pts (age 18-64 years) at 48 U.S. sites. Eligible pts (<3 spontaneous bowel movements [SBM]/week [wk] during a 2-wk baseline) were randomized to receive TD 5108 15, 30, or 50 mg, or PBO once daily for 4 wks. Bowel function and clinical symptoms were recorded using a daily interactive voice response system and a range of response definitions were applied to the comparison with placebo. Results: Treatment groups were balanced for baseline characteristics. The average (avg) numbers of SBM and complete SBM (CSBM) at baseline were 1.2 and 0.25/wk, respectively. Analyses of the response definitions are summarized below (n= number of patients treated for at least 7 days). Response rates using each definition were significantly greater than placebo for all TD-5108 doses. The lowest PBO response rates (< 10%) were seen with definitions that incorporated CSBM frequency ≥ 3/wk; these response definitions were also associated with the greatest differences between TD-5108 and PBO— 5-fold or greater. Conclusion: In this study in pts with CIC treated for 4 wks, the percent response to TD-5108 was greater than that to placebo regardless of response definition. The most robust differentiation of responses to TD 5108 vs PBO was achieved with response definitions incorporating ≥ 3CSBM/wk.