Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1)

Abstract

Objectives: Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with constipation-predominant irritable bowel syndrome (IBS-C).

Methods: In this phase 3, double-blind study (ClinicalTrials.gov identifier NCT02621892), patients with IBS-C were randomized to tenapanor 50 mg b.i.d. or placebo b.i.d. for 12 weeks followed by a 4-week randomized withdrawal period. The primary efficacy variable was the proportion of patients who reported a reduction in average weekly worst abdominal pain of ≥30.0% and an increase of ≥1 complete spontaneous bowel movement from baseline, both in the same week, for ≥6 weeks of the 12-week treatment period.

Results: Of the 629 randomized patients with IBS-C, 606 (96.3%) were included in the intention-to-treat analysis set (tenapanor: n = 307; placebo: n = 299) and 533 (84.7%) completed the 12-week treatment period. In the intention-to-treat analysis set (mean age 45 years, 81.4% women), a significantly greater proportion of patients treated with tenapanor met the primary endpoint than patients treated with placebo (27.0% vs 18.7%, P = 0.020). Abdominal symptoms and global symptoms of IBS also improved with tenapanor (P < 0.05 vs placebo). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in 6.5% and 0.7% of patients receiving tenapanor and placebo, respectively, during the 12-week treatment period.

Discussion: Tenapanor 50 mg b.i.d. improved IBS-C symptoms and was generally well tolerated, offering a potential new treatment option for patients with IBS-C.

Conflict of interest statement

Guarantor of the article: William D. Chey, MD, AGAF, FACG, FACP, RFF.

Specific author contributions: W.D.C. and A.J.L. contributed to the planning of the study, interpretation of the data, and critical revision of the manuscript for important intellectual content; D.P.R. contributed to the planning of the study, conduct of the study, interpretation of the data, and critical revision of the manuscript for important intellectual content; all authors approved the final version of the manuscript for submission.

Financial support: Medical writing support was provided by Svetha Sankar, BSc BVMS, and Steven Inglis, PhD, of Oxford PharmaGenesis and was funded by Ardelyx.

Potential competing interests: W.D.C. is a consultant for Allergan, Biomerica, IM Health, Ironwood, Outpost, Prometheus, QOL Medical, Ritter Pharmaceuticals, and Salix/Valeant and has received research funding from Ardelyx, Biomerica, Commonwealth Diagnostics International, Ironwood, Nestlé, QOL Medical, Salix/Valeant, Vibrant, and Zespri. A.J.L. is a consultant for Allergan, Ardelyx, Bioamerica, Ironwood, Prometheus, and Valeant and has received research funding from Prometheus, Bioamerica, Vibrant, and Ironwood. D.P.R. is an employee of, and has ownership interest in, Ardelyx, Inc.

Figures

Figure 1.

Overview of patient flow through the study. The safety analysis set includes all patients who received ≥1 dose of treatment. The ITT analysis set includes all patients who met the study entry inclusion/exclusion criteria, were randomized, and received ≥1 dose of the study drug. b.i.d., twice daily; ITT, intention-to-treat; PRO, patient-reported outcome.

Figure 2.

Six- of 12-week responder rates (ITT analysis set): proportions of patients with (a) combined response for ≥6 of the 12 treatment weeks (primary efficacy variable), (b) abdominal pain response for ≥6 of 12 treatment weeks (key secondary efficacy variable), and (c) CSBM response for ≥6 of 12 treatment weeks (key secondary efficacy variable). aThe adjusted RR was based on the ratio of responder rates for tenapanor 50 mg b.i.d. vs placebo b.i.d., stratified by pooled investigator sites using the Mantel–Haenszel method. bThe CMH P value was based on a 1 degree of freedom test for association between treatment (tenapanor and placebo), stratified by pooled investigator sites. An abdominal pain response is defined as a decrease in average weekly worst abdominal pain of ≥30.0% from baseline. A CSBM response is defined as an increase of ≥1 CSBM/week from baseline. A combined response is defined as an abdominal pain response and CSBM response both occurring in the same week. b.i.d., twice daily; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; CSBM, complete spontaneous bowel movement; ITT, intention-to-treat; RR, relative risk.

Figure 3.

Nine- of 12-week responder rates (ITT analysis set): proportions of patients with (a) combined response for ≥9 of 12 treatment weeks (key secondary efficacy variable), (b) abdominal pain response for ≥9 of 12 treatment weeks (key secondary efficacy variable), and (c) CSBM response for ≥9 of 12 treatment weeks (key secondary efficacy variable). aThe adjusted RR was based on the ratio of responder rates for tenapanor 50 mg b.i.d. vs placebo b.i.d., stratified by pooled investigator sites using the Mantel–Haenszel method. bThe CMH P value was based on a 1 degree of freedom test for association between treatment (tenapanor and placebo), stratified by pooled investigator sites. An abdominal pain response is defined as a decrease in average weekly worst abdominal pain of ≥30.0% from baseline. A CSBM response is defined as an increase of ≥1 CSBM/week from baseline. A combined response is defined as an abdominal pain response and CSBM response both occurring in the same week. b.i.d., twice daily; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; CSBM, complete spontaneous bowel movement; ITT, intention-to-treat; RR, relative risk.

Figure 4.

Durable responder rates (ITT analysis set): proportions of patients with (a) durable combined response (secondary efficacy variable), (b) durable abdominal pain response (secondary efficacy variable), and (c) durable CSBM response (secondary efficacy variable). aThe adjusted RR was based on the ratio of responder rates for tenapanor 50 mg b.i.d. vs placebo b.i.d., stratified by pooled investigator sites using the Mantel–Haenszel method. bThe CMH P value was based on a 1 degree of freedom test for association between treatment (tenapanor and placebo), stratified by pooled investigator sites. A durable abdominal pain response is defined as a decrease in average weekly worst abdominal pain of ≥30.0% from baseline for ≥9 of 12 treatment weeks, including ≥3 of the final 4 weeks of the treatment period. A durable CSBM response is defined as an increase of ≥1 CSBM/week from baseline for ≥9 of 12 treatment weeks, including ≥3 of the final 4 weeks of the treatment period. A durable combined response is defined as an abdominal pain response and CSBM response, both occurring in the same week, for ≥9 of 12 treatment weeks, including ≥3 of the final 4 weeks of the treatment period. b.i.d., twice daily; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; CSBM, complete spontaneous bowel movement; ITT, intention-to-treat; RR, relative risk.

Figure 5.

Mean change from baseline in average weekly number of CSBMs over time (ITT analysis set) during the (a) treatment period and (b) RW period. *P < 0.001, †P = 0.001 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. Baseline for the treatment period is defined as the average of the first and second weeks of the screening period. Baseline for the RW period is defined as the last valid week of the treatment period. A valid week required at least 4 days of SBM reporting. b.i.d., twice daily; CSBM, complete spontaneous bowel movement; ITT, intention-to-treat; RW, randomized withdrawal.

Figure 6.

Mean percentage change from baseline in average weekly abdominal pain score over time (ITT analysis set) during the (a) treatment period and (b) RW period. *P < 0.05, †P < 0.001 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. Baseline for the treatment period is defined as the average of the first and second weeks of the screening period. Baseline for the RW period is defined as the last valid week of the treatment period. A valid week required at least 4 days of abdominal pain reporting. b.i.d., twice daily; ITT, intention-to-treat; RW, randomized withdrawal.