INTRODUCTION
Irritable bowel syndrome (IBS) is a chronic, symptom-based disorder characterized by abdominal pain and altered bowel movements (1 1,2 2
The pathogenesis of IBS is believed to be heterogeneous, potentially involving abnormalities in gut motility, visceral sensation, gut microbiota, intestinal permeability, and/or gut immune activation (2 1,3
Although dietary interventions and over-the-counter medicines can improve bowel movement frequency and stool consistency in patients with IBS-C, symptoms such as abdominal pain and bloating often remain unaddressed (3–5 6,7 8–10
Tenapanor, which has recently been approved by the US Food and Drug Administration (FDA) for the treatment of IBS-C, is a first-in-class, minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3; Figure 1 ), expressed on the luminal surface throughout the small intestine and proximal colon (11 12 13,14 ClinicalTrials.gov 15 15
Figure 1.: Mechanism of action. Tenapanor inhibits NHE3, which transports luminal sodium in exchange for cellular protons. NHE3, sodium/hydrogen exchanger isoform 3.
The current study, T3MPO-2, was designed to evaluate the efficacy and safety of tenapanor 50 mg b.i.d. compared with placebo over 26 weeks in patients with IBS-C.
METHODS
Study design
T3MPO-2 (ClinicalTrials.gov
Patients recorded data on efficacy variables, including daily bowel movement frequency and abdominal symptoms, using a touch-tone telephone diary with an interactive voice response system (IVRS).
The study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before study entry. All participating sites obtained independent ethics committee/institutional review board approval.
Patients
Full inclusion, exclusion, and study entry criteria used in this trial have been described previously (15 16
To be randomly assigned to study treatment, patients also had to complete their IVRS telephone diary on ≥11 of 14 days during the 2-week screening period to demonstrate diary adherence and the following outcomes: weekly stool frequency of ≤5 spontaneous bowel movements (SBMs; defined as bowel movements occurring without the use of a laxative within the preceding 24 hours) and <3 complete spontaneous bowel movements (CSBMs; defined as SBMs accompanied by a sensation of complete evacuation); average weekly stool consistency score of <3 using the Bristol Stool Form Scale (BSFS) (17
Rescue medications
Rescue medication use (bisacodyl 5 mg oral tablet or 10 mg suppository) was permitted for no more than 2 of the 14 screening period days and was not permitted within 48 hours of being randomly assigned to the study treatments. Throughout the treatment period, rescue medication was permitted to relieve severe constipation, defined as ≥72 hours without a bowel movement or when symptoms became intolerable. A bowel movement was not considered to be “spontaneous” if it was reported within 24 hours of the use of a rescue medication.
Efficacy variables and assessments
The primary endpoint was the 6/12-week combined responder rate, defined as the proportion of patients who had a weekly combined response for ≥6 of the first 12 weeks of the treatment period. A weekly combined response was defined as a decrease in average weekly worst abdominal pain of ≥30.0% from baseline (abdominal pain response) and an increase of ≥1 weekly CSBM from baseline (CSBM response), both in the same week. Baseline was defined as the average of values obtained during the 2-week screening period (i.e., weeks −1 and −2).
Key secondary endpoints included the 6/12-week CSBM and abdominal pain responder rates, the 9/12-week combined responder rate (the proportion of patients with a weekly combined response and ≥3 average weekly CSBMs for at least 9 of the first 12 weeks of the treatment period), and the 13/26-week combined responder rate (the proportion of patients with a weekly combined response for at least 13 weeks of the 26-week treatment period). Other secondary endpoints included “durable” combined CSBM and abdominal pain responder rates (the proportion of patients with a 9/12-week combined response who also met the response criteria for at least 3 of the final 4 weeks of the first 12 weeks of the treatment period); weekly proportion of patients with ≥3 CSBMs; average weekly CSBMs, SBMs, stool consistency, and straining score; 6/12-, 9/12-, and 13/26-week responder rates for abdominal symptoms (discomfort, bloating, cramping, and fullness); weekly IBS severity and constipation severity scores; weekly adequate relief and degree of relief of IBS symptoms; HRQoL assessed using the Irritable Bowel Syndrome Quality of Life questionnaire (IBS-QOL); and treatment satisfaction.
Patients recorded data for all efficacy variables using the IVRS telephone diary. Variables recorded daily included the frequency and time of each bowel movement, sensation of complete bowel emptying (1 = yes, 2 = no), stool consistency (measured using the BSFS), abdominal symptom scores (pain, bloating, cramping, discomfort, and fullness; each on a 0–10-point scale: 0 = absent, and 10 = very severe), straining score (1–5-point scale: 1 = not at all and 5 = an extreme amount), and use and time of rescue medication. Variables scored weekly included constipation severity, IBS severity (each on a 1–5-point scale: 1 = none and 5 = very severe), adequate relief of IBS (1 = yes and 2 = no), degree of relief from IBS symptoms (1–7-point scale: 1 = completely relieved and 7 = as bad as I can imagine), and treatment satisfaction (1–5-point scale: 1 = not at all satisfied and 5 = very satisfied). Patients were asked to complete the IBS-QOL at randomization (day 1) and at treatment weeks 12 and 26.
Safety outcomes and assessments
Safety assessments were based on AEs (all visits), clinical laboratory tests, comprising serum chemistry, hematology, and urinalysis (weeks −2, 4, 12, and 26), vital signs (weeks −2, 12, and 26), electrocardiograms (ECGs; weeks −2, 12, and 26), and physical examinations (weeks −2 and 26), as described previously (15
AEs were spontaneously reported by the patient and/or disclosed in response to an open question from study personnel or revealed by observation, physical examination, or other diagnostic procedures. Investigators defined AEs as mild (the event does not interfere in a significant manner with the patient's normal functioning level; it may be an annoyance but does not cause any limitation in usual activity), moderate (the event produces some impairment of functioning but is not hazardous to health; it is uncomfortable or an embarrassment and may cause some limitation in usual activity), or severe (the event produces significant impairment or incapacitation and is a definite hazard to the subject's health). All AEs were recorded on the appropriate page of the electronic case report form.
Statistical methods
Scores for weekly SBMs and weekly CSBMs were standardized to 7-day frequencies, with missing days during the week being imputed with the average for the recorded days. A valid week required ≥4 recorded diary days; patients with <4 days' input were treated as nonresponders for that week.
All patients who met the study eligibility criteria, were randomized, and received ≥1 dose of study drug were included in the intention-to-treat (ITT) analysis set. The ITT analysis set was used for the evaluation of all efficacy variables. All patients who received ≥1 dose of study drug were included in all analyses of safety data (safety analysis set).
A sample size of 300 in each treatment group was expected to achieve 95% power to detect a difference of 0.15 (15.0%) in the 6/12-week combined responder rate (primary endpoint) between the tenapanor and placebo groups. This assumed (under the alternative hypothesis) that the 6/12-week combined responder rate in the tenapanor group would be ≥45.0% and no closer than 15.0% to that in the placebo group.
All efficacy variables involving responder rates or proportions were analyzed using a Cochran–Mantel–Haenszel test with pooled investigator site as a stratification (adjustment) variable. All changes from baseline in continuous efficacy variables derived from the daily IVRS telephone diary, and the weekly IBS severity, constipation severity, and IBS-QOL data, were analyzed using an analysis of covariance model, with terms for pooled investigator site and treatment and baseline values as the covariates. The degrees of relief of IBS symptoms and treatment satisfaction were analyzed using an analysis of variance model, with terms for pooled investigator site and treatment as the covariates. Statistical analyses were performed using a 2-sided significance level of 0.050.
RESULTS
Patients
Of 1,461 patients who were screened, 620 (42.4%) were randomly assigned to treatment with tenapanor or placebo for 26 weeks (Figure 2 ). In total, 593 patients were included in the ITT and safety analysis sets, of whom 293 received tenapanor and 300 received placebo. Patients who were randomized but excluded from the ITT and safety analysis sets (n = 27) were associated with a clinical site judged by the sponsor to be in serious breach of Good Clinical Practice. At the time the breach was identified, 21 of these 27 patients had completed the study and 6 had discontinued (consent withdrawn, lost to follow up or citing other reasons).
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.
The entire 26-week treatment period was completed by 232 of the 306 patients (75.8%) assigned to tenapanor and by 249 of the 314 patients (79.3%) assigned to placebo. Treatment groups were well balanced regarding patient demographics and baseline IBS-related characteristics (Table 1 ). The mean age of patients was 45.4 years, with most patients being women (82.1%) and White (63.6%).
Table 1.: Patient demographics and baseline IBS-related characteristics (ITT analysis set)
Efficacy
A significantly greater proportion of patients in the tenapanor treatment group were 6/12-week combined responders than those in the placebo group (primary endpoint; 36.5% vs 23.7%; P < 0.001; Figure 3a ). The 6/12-week abdominal pain responder rate was also significantly higher with tenapanor treatment than with placebo (49.8% vs 38.3%; P = 0.004; Figure 3b ). Similarly, a significantly greater proportion of patients in the tenapanor treatment group were 6/12-week CSBM responders than those in the placebo group (47.4% vs 33.3%; P < 0.001; Figure 3c ).
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). a The 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. b The 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.
The 9/12-week combined responder rate was also significantly higher for patients receiving tenapanor than for those receiving placebo (18.4% vs 5.3%; P < 0.001; Figure 4a ). Likewise, a significantly greater proportion of patients in the tenapanor treatment group than those in the placebo group were 9/12-week abdominal pain responders (35.8% vs 26.7%; P = 0.015; Figure 4b ) and 9/12-week CSBM responders (22.2% vs 6.0%; P < 0.001; Figure 4c ). Compared with the placebo group, a significantly greater proportion of patients in the tenapanor treatment group were 13/26-week combined responders (35.5% vs 24.3%; P = 0.003; Figure 5a ). Similarly, a significantly greater proportion of patients in the tenapanor treatment group than those in the placebo group were 13/26-week abdominal pain responders (50.2% vs 40.0%; P = 0.013; Figure 5b ) and 13/26-week CSBM responders (41.3% vs 31.0%; P = 0.010; Figure 5c ).
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. a The 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. b The 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.: 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. a The 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. b The 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.
The durable combined responder rate was significantly higher with tenapanor treatment than with placebo (18.1% vs 5.0% for placebo; P < 0.001; Figure 6a ). A significantly greater proportion of patients in the tenapanor treatment group than those in the placebo group were also durable abdominal pain responders (34.8% vs 26.7%; P = 0.028; Figure 6b ) and durable CSBM responders (21.2% vs 5.7%; P < 0.001; Figure 6c ). Compared with placebo, patients treated with tenapanor had a significantly greater mean increase from baseline in the average weekly number of CSBMs (P < 0.001; Figure 7 ) and a significantly greater mean decrease from baseline in average weekly abdominal pain scores (P < 0.01; Figure 8 ), from week 1 onward. A greater proportion of patients receiving tenapanor also met other secondary endpoints than patients receiving placebo (see Tables 1 and 2, Supplementary Digital Content 2, https://links.lww.com/AJG/B789 P = 0.011).
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. a The 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. b The 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.: 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.: 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.
During the treatment period, 117 patients (39.9%) in the tenapanor group and 155 patients (51.7%) in the placebo group reported rescue medication use. The number of patients reporting the use of rescue medication generally decreased in both treatment groups over the course of the treatment period.
Safety
Mean study drug adherence in the safety analysis set was 98.1% for tenapanor and 99.2% for placebo during the treatment period. Most patients in the tenapanor group (93.5%) and the placebo group (93.3%) demonstrated a greater than 80% adherence rate.
Table 2 gives an overview of the AEs that occurred during the treatment period. Four patients in the tenapanor group experienced serious AEs (SAEs). By the preferred term, the SAEs were abdominal pain, diarrhea, nausea, and chronic obstructive pulmonary disease. Only the SAE of diarrhea reported in the tenapanor group was judged to be “possibly related” to treatment. No deaths occurred over the course of the study.
Table 2.: Overview of AEs (safety analysis set)
Treatment-related AEs were reported for 64 patients (21.8%) receiving tenapanor and 28 patients (9.3%) receiving placebo during the 26-week treatment period. By system organ class, most treatment-related AEs were gastrointestinal in nature, with diarrhea, abdominal distension, and flatulence the only treatment-related AEs by the preferred term reported for ≥3.0% of patients receiving tenapanor. Diarrhea was the most common AE, by the preferred term, and was reported by 47 patients (16.0%) receiving tenapanor and 11 patients (3.7%) receiving placebo during the treatment period. Diarrhea was typically transient (≤1 week's duration) and mild to moderate in severity. In approximately half of the cases, diarrhea occurred within a week of treatment commencement, and two-thirds of cases occurred within the first 3 weeks of treatment. Diarrhea was judged to be treatment related in 44 patients (15.0%) in the tenapanor group and 8 patients (2.7%) in the placebo group and led to study drug discontinuation for 19 patients (6.5%) in the tenapanor group and 2 patients (0.7%) in the placebo group. Generally, there was no evidence of clinically significant differences between treatment groups in electrolytes and other laboratory parameters (serum chemistry, hematology, and urinalysis parameters), ECG parameters, vital signs, and physical examinations during the study.
DISCUSSION
In this randomized, phase 3 study, tenapanor treatment significantly improved IBS-C symptoms compared with placebo, with no evidence of decreasing efficacy over the 26-week study period. Compared with placebo, a significantly higher proportion of patients receiving tenapanor experienced an increase in CSBM frequency and a reduction in abdominal pain in the same week for ≥6 of the first 12 weeks of the treatment period (the primary endpoint). A statistically significant difference between tenapanor and placebo was also achieved for the more stringent endpoints requiring ≥9/12 and ≥13/26 treatment weeks of combined response. Overall, our study confirms the results from the previously published phase 3 T3MPO-1 trial, which assessed the effects of 12 weeks of tenapanor treatment in patients with IBS-C (13 8,9,18,19
In both T3MPO-1 and T3MPO-2, robust improvements in average weekly CSBMs and abdominal pain were observed by week 1 and maintained through to the end of the treatment period (15 20
A significantly greater proportion of patients receiving tenapanor experienced improvements in abdominal symptoms (discomfort, bloating, cramping, and fullness) for ≥6 and ≥9 of the first 12 weeks, and ≥13 of 26 weeks of the treatment period than those receiving placebo. Similarly, patients receiving tenapanor had a significantly greater improvement in global IBS treatment measures than those receiving placebo. Notably, patients receiving tenapanor reported a significant improvement from baseline in treatment satisfaction at week 26 compared with placebo. At the 26-week time point, 80.5% of patients receiving tenapanor were at least moderately satisfied with their treatment, compared with 61.2% of patients receiving placebo. The benefits of tenapanor in patients with IBS-C were also seen for quality of life parameters, with clinically meaningful improvements observed at weeks 12 and 26 across all IBS-QOL subscales, although these improvements were not always statistically significant compared with placebo.
Overall, tenapanor was associated with an acceptable safety profile over the course of our study, consistent with the results of previously reported phase 2b and 12-week phase 3 trials (15,21 ClinicalTrials.gov
Potential limitations of the study should be acknowledged. Related to the timing of the study, the Rome III criteria, rather than the current Rome IV criteria, were used to identify patients for this study. However, recent research suggests that most patients fulfilling the Rome III criteria will also fulfill the Rome IV criteria for IBS-C (22 8–10 23 24
In conclusion, this methodologically rigorous, randomized, placebo-controlled phase 3 trial demonstrates the efficacy and tolerability of tenapanor over 26 weeks in patients with IBS-C. The results from T3MPO-2, together with T3MPO-1, provided robust support for the recent FDA approval of tenapanor for the treatment of IBS-C. Tenapanor is an effective and generally well tolerated new treatment option for patients with IBS-C.
CONFLICTS OF INTEREST
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.Study Highlights
WHAT IS KNOWN
✓ People living with IBS-C can suffer considerable morbidity owing to abdominal and bowel symptoms.
✓ There are few evidence-based treatments that address the spectrum of IBS-C symptoms.
✓ Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3.
✓ In a previously published 12-week phase 3 study, a significantly greater proportion of patients with IBS-C reported a combined response, consisting of improvements in abdominal pain and stool frequency, when treated with tenapanor compared with placebo.
WHAT IS NEW HERE
✓ Consistent with the previously published phase 3 trial, tenapanor improved the combined response rate for at least 6 and 9 of the first 12 weeks, relative to placebo.
✓ Tenapanor also improved combined response rates for at least 13 of 26 weeks, compared with placebo.
✓ Tenapanor was generally well tolerated for up to 26 weeks; the most common adverse event was transient and mildto-moderate diarrhea.
ACKNOWLEDGMENTS
We would like to thank the patients and their physicians who participated in the study. Medical writing support was provided by Svetha Sankar, BSc, BVMS, and Michael Molloy-Bland, BSc, MSc, PhD, of Oxford PharmaGenesis Pty Ltd and was funded by Ardelyx.
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