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Randomized Controlled Trial
. 2024 May 1;119(5):937-945.
doi: 10.14309/ajg.0000000000002685. Epub 2024 Jan 31.

Abdominal Symptom Improvement During Clinical Trials of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis

Anthony J Lembo  1 , William D Chey  2 , Lucinda A Harris  3 , Rosita Frazier  3 , Darren M Brenner  4 , Lin Chang  5 , Brian E Lacy  6 , Susan Edelstein  7 , Yang Yang  7 , Suling Zhao  7 , David P Rosenbaum  7
Affiliations
Randomized Controlled Trial

Abdominal Symptom Improvement During Clinical Trials of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis

Anthony J Lembo et al. Am J Gastroenterol. .

Abstract

Introduction: This post hoc analysis evaluated the efficacy of tenapanor on abdominal symptoms in patients with irritable bowel syndrome with constipation. Abdominal symptoms assessed included pain, discomfort, bloating, cramping, and fullness.

Methods: The abdominal symptom data were pooled from 3 randomized controlled trials (NCT01923428, T3MPO-1 [NCT02621892], and T3MPO-2 [NCT02686138]). Weekly scores were calculated for each abdominal symptom, and the Abdominal Score (AS) was derived as the average of weekly scores for abdominal pain, discomfort, and bloating. The overall change from baseline during the 12 weeks was assessed for each symptom weekly score and the AS. The AS 6/12-week and 9/12-week response rates (AS improvement of ≥2 points for ≥6/12- or ≥9/12-week) were also evaluated. The association of weekly AS response status (reduction of ≥30%) with weekly complete spontaneous bowel movement (CSBM) status (=0 and >0) was assessed.

Results: Among 1,372 patients (684 tenapanor [50 mg twice a day] and 688 placebo), the least squares mean change from baseline in AS was -2.66 for tenapanor vs -2.09 for placebo ( P < 0.0001). The 6/12-week AS response rate was 44.4% for tenapanor vs 32.4% for placebo ( P < 0.0001), and for 9/12-week AS, 30.6% for tenapanor vs 20.5% for placebo ( P < 0.0001). A significant association between weekly CSBM status and weekly AS response status was observed each week ( P < 0.0001), with a greater proportion achieving an AS reduction in patients with >0 CSBMs in a week.

Discussion: Tenapanor significantly reduced abdominal symptoms in patients with irritable bowel syndrome with constipation, particularly pain, discomfort, and bloating measured by AS, compared with placebo.

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Conflict of interest statement

Guarantor of the article: David P. Rosenbaum, PhD.

Specific author contributions: A.J.L., W.D.C., L.A.H., R.F., D.M.B., L.C., and B.E.L. were responsible for data curation and investigation. D.P.R., Y.Y., S.Z., and S.E. conceptualized the study. Y.Y. and S.Z. were responsible for the formal analysis and reviewed the manuscript critically for statistical content. A.J.L., W.D.C., L.A.H., R.F., D.M.B., L.C., B.E.L., D.P.R., and S.E. contributed to the critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript for submission.

Financial support: This study was funded by Ardelyx.

Potential competing interests: A.J.L. is a consultant for Allergan, Ardelyx, Atmo, Allakos, BioAmerica, AEON, Arena, Takeda, Evoke Pharma, Ironwood Pharmaceuticals, Aeon, Gemelli, Alkermes, Pfizer, OrthoMed, and Vibrant and has stock with Johnson & Johnson, Bristol Myer Squibb, and Allurion. W.D.C. is a consultant for Abbvie, Ardelyx, Arena, Baush, Biomerica, Gemelli, Ironwood, Isothrive, Nestle, Progenity, Salix, Takeda, Urovant, and Vibrant and has stock options with GI on Demand/Gastro Girl, Isothrive, and Modify Health. L.A.H. has received financial support from Ardelyx, AbbVie, Alnylam, Ironwood, Gemelli Biotech, Salix, and Takeda. R.F. has no conflict of interest. D.M.B. is a consultant, advisor, and/or speaker for Anji, Ardelyx, Abbive, Alnylam, Salix, Ironwood, Takeda, Bayer, Redhill, Mahana, Laborie, Owlstone, Entrinsic Bioscience, Vibrant and is a member of the Board of Directors of the International Foundation for GI Disorders (IFFGD). L.C. has served as a member of the scientific advisory boards for Ardelyx, Atmo, Immunic, Ironwood, and Vibrant. She has served as a consultant for Bausche Health, Food Marble, and Trellus Health and a speaker for Abbvie. She has received research support from Arena, AnX Robotica, and Ironwood. She has stock options with Food Marble, ModifyHealth, and Trellus Health. B.E.L. is a consultant for Allakos, Allergan, Arena, Cosmos, Ironwood, Salix, and Viver. D.P.R., Y.Y., S.Z., and S.E. are employees of Ardelyx.

Clinical trials: NCT01923428: The Efficacy of AZD1722 in Constipation Predominant Irritable Bowel Syndrome (IBS-C). NCT02621892: A 12-Week Study With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Tenapanor for the Treatment of IBS-C (T3MPO-1). NCT02686138: A 26-Week Study to Evaluate the Efficacy and Safety of Tenapanor in IBS-C (T3MPO-2).

Figures

Figure 1.
Figure 1.
Raw mean change from baseline in average weekly score of each abdominal symptom over the first 12 weeks of treatment (pooled population). (a) Abdominal pain, (b) abdominal discomfort, (c) abdominal bloating, (d) abdominal cramping, and (e) abdominal fullness. Error bars represent standard error. n, the number of patients included in the summary in the corresponding study week.
Figure 2.
Figure 2.
LS mean change from baseline in Abdominal Score over the first 12 weeks of treatment (pooled population). Error bars represent SE. LS mean, SE, and P values came from an unstructured MMRM with fixed-effect factors of treatment, week, and treatment-by-week; fixed-effect covariates of baseline Abdominal Score and baseline-by-week; and patient as a random effect. ****P < 0.0001. Abdominal Score was defined as the mean of weekly scores for abdominal pain, discomfort, and bloating. LS, least squares; MMRM, mixed-effects model with repeated measures; n, the number of patients included in the summary in the corresponding study week.
Figure 3.
Figure 3.
Cumulative distribution function of change from baseline to week 12 in Abdominal Score (pooled population). The cumulative distribution function plot illustrates the percentage of patients (y-axis) achieving a certain level of response as assessed by the change from baseline in Abdominal Score (x-axis). This plot shows that the tenapanor group had a consistently higher percentage of patients achieving a certain level of response compared with the placebo group, supporting the efficacy of tenapanor. Negative values of change from baseline are indicative of improvement, whereas positive values indicate worsening. aEstimated P-value comparing the cumulative distribution functions between treatment arms was obtained from a Wilcoxon 2-sample test. Abdominal Score was defined as the average of weekly scores for abdominal pain, discomfort, and bloating.
Figure 4.
Figure 4.
Weekly Abdominal Score response rate over the first 12 weeks of treatment (pooled population). The weekly Abdominal Score response was defined as achieving a reduction from baseline of ≥2 points in Abdominal Score for a given postbaseline week. The response rate was analyzed using the Pearson χ2 test with a worst-case imputation approach (patients with missing data included and assumed to have no response). ****P < 0.0001. The Abdominal Score was defined as the average of weekly scores for abdominal pain, discomfort, and bloating.
Figure 5.
Figure 5.
Six of 12-week and 9 of 12-week Abdominal Score response rates (pooled population). The 6 of 12- or 9 of 12-week Abdominal Score response was defined as achieving weekly Abdominal Score response with ≥2-point reduction in a week for ≥6 or 9 weeks of the first 12 weeks of treatment. Response rates were analyzed using the Pearson χ2 test with a worst-case imputation approach (patients with missing data included and assumed to have no response). P values were obtained from Pearson χ2 tests. The Abdominal Score was defined as the average of weekly scores for abdominal pain, discomfort, and bloating. AS, Abdominal Score.
Figure 6.
Figure 6.
Association of weekly Abdominal Score response status with weekly CSBM status. The weekly Abdominal Score response was defined as achieving a reduction of ≥30% in Abdominal Score for a given postbaseline week. Weekly CSBM status = 0 (a) or > 0 (b) for a given postbaseline week. The association of weekly Abdominal Score status with the weekly CSBM status was assessed using the Cochran-Mantel-Haenszel test. The Abdominal Score was defined as the average of weekly scores for abdominal pain, discomfort, and bloating. n, number of patients included in the summary in the corresponding study week. CSBM, complete spontaneous bowel movement.
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