Tenapanor Treatment of Patients With Constipation-Predominant Irritable Bowel Syndrome: A Phase 2, Randomized, Placebo-Controlled Efficacy and Safety Trial

Abstract

Objectives: Tenapanor is a first-in-class, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger NHE3. This study assessed the efficacy and safety of tenapanor in patients with constipation-predominant irritable bowel syndrome (IBS-C).

Methods: In this phase 2, double-blind study, patients with IBS-C (Rome III criteria) were randomized (1:1:1:1) to receive tenapanor 5 mg, 20 mg, or 50 mg b.i.d., or placebo b.i.d. for 12 weeks. The primary end point was the complete spontaneous bowel movement (CSBM) responder rate, defined as the proportion of patients reporting an increase from baseline of ≥1 CSBM/week for ≥6/12 treatment weeks. Secondary end points included abdominal symptom responder rates (≥30% score improvement from baseline for ≥6/12 weeks) and a composite responder rate (CSBM and abdominal pain response in the same week for ≥6/12 weeks).

Results: Overall, 356 patients were randomized (mean age: 45.7 years; 86.8% women) and 304 completed the study. The CSBM responder rate was significantly higher in the tenapanor 50 mg b.i.d. group than in the placebo group (60.7 vs. 33.7%; P<0.001), as was the composite responder rate (50.0 vs. 23.6%; P<0.001). Responder rates for abdominal symptoms (pain, discomfort, bloating, cramping, and fullness) were significantly higher in the tenapanor 50 mg b.i.d. group than in the placebo group (all P<0.05). Diarrhea was the most frequent adverse event (tenapanor b.i.d.: 20 mg, 12.4%; 50 mg, 11.2%).

Conclusions: Tenapanor 50 mg b.i.d. significantly increased stool frequency and reduced abdominal symptoms in patients with IBS-C. Further research into tenapanor as a potential treatment for these patients is justified.

Figure 1

Overview of patient flow through the study. The safety analysis set includes all patients who received at least one dose of treatment. The ITT analysis set includes all patients who received at least one dose of treatment and for whom study assessment data had been collected for a minimum of 4 days. b.i.d., twice daily; ITT, intention to treat.

Figure 2

Responder rates: proportion of patients with: (a) an increase of at least one CSBM/week from baseline for at least 6 of 12 treatment weeks (CSBM responder rate—primary efficacy variable), (b) a decrease in abdominal pain of at least 30% from baseline for at least 6 out of 12 treatment weeks (abdominal pain responder rate), and (c) a decrease in abdominal pain of at least 30% and an increase of at least one CSBM/week (both in the same week) vs. baseline for at least 6 out of 12 treatment weeks (composite responder rate). ^aCMH screening test P value was based on a two degrees of freedom test for association between treatment (placebo, tenapanor 20 mg b.i.d., or tenapanor 50 mg b.i.d.) and responder rate, stratified by pooled investigator sites. ^bThe adjusted RR was based on the ratio of responder rates for placebo vs. each tenapanor treatment group, stratified by pooled investigator sites. ^cThe CMH P value was based on a one degree of freedom test for association between treatment and responder rate (placebo paired with each tenapanor treatment group separately), stratified by pooled investigator sites. b.i.d., twice daily; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; CSBM, complete spontaneous bowel movement; RR, relative risk.

Figure 3

Mean average weekly number of CSBMs over time (intention to treat analysis set). *P<0.050, tenapanor 50 mg b.i.d. vs. placebo. ^†P<0.050, tenapanor 20 mg b.i.d. and tenapanor 50 mg b.i.d. vs. placebo. P values were based on an analysis of covariance model with treatment and pooled investigator site as factors and baseline value as a covariate. b.i.d., twice daily; CSBM, complete spontaneous bowel movement.