Efficacy and Safety of Tenapanor in Patients With Constipation Predominant Irritable Bowel Syndrome: A 12-week, Double-Blind, Placebo-Controlled, Randomized Phase 3 Trial

Abstract

Introduction: Tenapanor is a locally acting, small-molecule inhibitor that selectively inhibits the intestinal sodium/hydrogen exchanger 3 (NHE3), thereby reducing sodium and phosphate uptake from the gut. In preclinical and clinical studies, tenapanor has been shown to reduce the absorption of dietary sodium and phosphorus. Tenapanor is an investigational drug being evaluated for the treatment of IBS-C and hyperphosphatemia in patients with ESRD on dialysis. Previously, tenapanor 50 mg twice daily significantly increased complete spontaneous bowel movement (CSBM) and abdominal pain responder rates (for 6 and 9 of 12 weeks) relative to placebo (NCT01923428). The aim of the present study was to evaluate the efficacy and safety of tenapanor 50 mg twice daily for the treatment of IBS-C. Methods: In this randomized, double-blind, placebo-controlled trial (NCT02621892), patients with IBS-C (modified Rome III criteria) with an average of<3 CSBM/week, ≤5 SBM (spontaneous bowel movement)/week, and abdominal pain ≥3 (0-10 rating scale) during a 2-week screening period were randomized to receive oral tenapanor 50 mg twice daily or placebo over a 12-week treatment period, followed by a 4-week randomized withdrawal period. The primary efficacy endpoint was the combined responder rate (≥30% abdominal pain reduction and ≥1 CSBM increase in the same week for ≥6 of 12 weeks). Responder analyses were performed over 12 weeks using the Cochran-Mantel-Haenszel test. Results: There were 606 patients in the intent-to-treat population (mean age, 45.0 years; 81.4% women). At baseline, the average CSBM was 0.2/week, and the average abdominal pain score was 6.3; all groups were similar at baseline. Compared with placebo (18.7%), significantly more patients taking tenapanor met the primary endpoint (27.0%; p=0.020) and demonstrated statistically significant improvements in four of five key secondary endpoints over the 12-week study (Table). Diarrhea was the most common adverse event during the treatment period (1.7%, placebo; 14.6%, tenapanor), causing discontinuation in 5.9% of patients who received tenapanor.Table: No Caption available.Conclusion: In patients with IBS-C, tenapanor 50 mg twice daily treatment resulted in statistically significant improvements in the primary combined responder endpoint (≥6 of 12 weeks). Significant benefits were also seen for ≥9 of 12 weeks in abdominal pain and stool frequency.