Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2)

William D Chey, Anthony J Lembo, Yang Yang, David P Rosenbaum, William D Chey, Anthony J Lembo, Yang Yang, David P Rosenbaum

Abstract

Introduction: 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 long-term efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with irritable bowel syndrome with constipation (IBS-C).

Methods: In this randomized double-blind study (ClinicalTrials.gov identifier: NCT02686138), patients with IBS-C received tenapanor 50 mg b.i.d. or placebo b.i.d. for 26 weeks. The primary endpoint was the proportion of patients who had a reduction of ≥30.0% in average weekly worst abdominal pain and an increase of ≥1 weekly complete spontaneous bowel movement from baseline, both in the same week, for ≥6 of the first 12 treatment weeks (6/12-week combined responder).

Results: Of the 620 randomized patients with IBS-C, 593 (95.6%) were included in the intention-to-treat analysis set (tenapanor: n = 293; placebo: n = 300) and 481 patients (77.6%) completed the 26-week treatment period. In the intention-to-treat analysis set (mean age: 45.4 years; 82.1% women), a significantly greater proportion of patients treated with tenapanor were 6/12-week combined responders than those treated with placebo (36.5% vs 23.7%; P < 0.001). Abdominal symptoms and global symptoms of IBS were significantly improved with tenapanor compared with placebo. Diarrhea, the most common adverse event, was typically transient and mild to moderate in severity. Diarrhea led to study drug discontinuation for 19 (6.5%) and 2 patients (0.7%) receiving tenapanor and placebo, respectively.

Discussion: Tenapanor 50 mg b.i.d. improved IBS-C symptoms over 26 weeks and was generally well tolerated, offering a potential new long-term treatment option for patients with IBS-C (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B797).

Trial registration: ClinicalTrials.gov NCT02621892 NCT02686138 NCT02727751.

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. Y.Y.: reviewed the manuscript critically for statistical content and contributed to the 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: Ardelyx was the sponsor of the study.

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

ClinicalTrials.gov identifier: NCT02686138.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.

Figures

Figure 1.
Figure 1.
Mechanism of action. Tenapanor inhibits NHE3, which transports luminal sodium in exchange for cellular protons. NHE3, sodium/hydrogen exchanger isoform 3.
Figure 2.
Figure 2.
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 study drug. b.i.d., twice daily; ITT, intention-to-treat; PRO, patient-reported outcome.
Figure 3.
Figure 3.
Six of 12-week responder rates (ITT analysis set): proportions of patients with (a) combined response for ≥6 of the first 12 treatment weeks (primary efficacy endpoint), (b) abdominal pain response for ≥6 of the first 12 treatment weeks (key secondary efficacy endpoint), and (c) CSBM response for ≥6 of the first 12 treatment weeks (key secondary efficacy endpoint). 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. 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.
Figure 4.
Nine of 12-week responder rates (ITT analysis set; key secondary efficacy endpoint): proportions of patients with (a) combined response and ≥3 average weekly CSBMs for ≥9 of the first 12 treatment weeks, (b) abdominal pain response for ≥9 of the first 12 treatment weeks, and (c) CSBM response and ≥3 average weekly CSBMs for ≥9 of the first 12 treatment weeks. 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. 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.
Figure 5.
Thirteen of 26-week responder rates (ITT analysis set; key secondary efficacy endpoint): Proportions of patients with (a) combined response for ≥13 of 26 treatment weeks, (b) abdominal pain response for ≥13 of 26 treatment weeks, and (c) CSBM response for ≥13 of 26 treatment weeks. 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. 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 6.
Figure 6.
Durable responder rates (ITT analysis set; other secondary efficacy endpoint): Proportions of patients with (a) durable combined response, (b) durable abdominal pain response, and (c) durable CSBM response. 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 the first 12 treatment weeks, including ≥3 of the final 4 weeks of the first 12 weeks of the treatment period. A durable CSBM response is defined as an increase of ≥1 CSBM/week from baseline and ≥3 CSBM/week for ≥9 of the first 12 treatment weeks, including ≥3 of the final 4 weeks of the first 12 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 7.
Figure 7.
Mean change from baseline in the average weekly number of CSBMs over time (ITT analysis set). P < 0.001 vs placebo for all time points. P values were based on an ANCOVA model with treatment and pooled investigator site as factors and baseline value as a covariate. ANCOVA, analysis of covariance; b.i.d., twice daily; CSBM, complete spontaneous bowel movement; ITT, intention-to-treat.
Figure 8.
Figure 8.
Mean change from baseline in the average weekly abdominal pain score over time (ITT analysis set). *P < 0.01, **P < 0.001 vs placebo. P values were based on an ANCOVA model with treatment and pooled investigator site as factors and baseline value as a covariate. ANCOVA, analysis of covariance; b.i.d., twice daily; ITT, intention-to-treat.

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