Effect of Menopausal Status Defined by Age on Treatment Efficacy in Women With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis of Pooled Phase 2b/3 Trials

Introduction: Irritable bowel syndrome (IBS) is a disorder of gut–brain interaction characterized by abdominal pain and changes in bowel habits. Although age and hormonal-related effects on IBS severity have been observed, the effect of menopause remains unclear and influence on response to therapies is unknown. This post hoc analysis explored the effects of linaclotide (LIN), a guanylate cyclase-C agonist, on women with IBS with constipation (IBS-C), stratified by menopausal status defined using age. Methods: Patient data from placebo (PBO)-controlled studies that assessed LIN efficacy in IBS-C were pooled from Phase 2b/3 trials. Female patients were grouped by age: ≤ 45 years (premenopausal) or > 45 years (postmenopausal). Pairwise t-tests compared endpoints across age and treatment groups for abdominal score,1 complete spontaneous bowel movement (CSBM) weekly frequency rate, and degree of relief of IBS symptoms score. Cochran–Mantel–Haenszel tests compared percentage of responders across age and treatment groups for abdominal pain and constipation (APC) +1, 30% improvement in abdominal pain, adequate relief of IBS symptoms, and degree of relief of IBS symptoms. Results: Of 1,593 female patients (PBO, n = 797; LIN, n = 796), mean ages were similar across PBO and LIN (≤ 45 years, 35 for both; > 45 years, 56 for both). Mean baseline values were similar across all endpoints (Figure 1). Significant improvements in abdominal score (PBO group) and CSBM/week (LIN group) were observed in patients aged > 45 vs ≤ 45 years. A numerically higher percentage of responders were observed for APC +1, 30% improvement in abdominal pain, and degree of relief of IBS symptoms in patients aged > 45 vs ≤ 45 years for both treatments; adequate relief was significantly higher (Table 1). Comparing treatment response within similar age groups, significant improvements were observed with LIN vs PBO for every efficacy and responder endpoint assessed (all P< 0.0001). Conclusion: In this post hoc analysis of age groups likely representing pre- and post-menopausal women with IBS-C, significantly greater abdominal (PBO group) and bowel (LIN group) symptom improvements in patients aged > 45 vs ≤ 45 years were observed. Significantly higher percentages of responders for adequate relief of IBS symptoms were exhibited in patients aged > 45 vs ≤ 45 years, regardless of treatment. Irrespective of age, LIN significantly improved all endpoints assessed vs PBO. Reference: Chang L, Lacy BE, Moshiree B, et al. Efficacy of Linaclotide in Reducing Abdominal Symptoms of Bloating, Discomfort, and Pain: A Phase 3B Trial Using a Novel Abdominal Scoring System. Am J Gastroenterol 2021;116(9):1929-1937Figure 1.: Efficacy Assessment for Female Patients by Age and Treatment Group Only patients with both baseline and week 12 assessments were included. CI, confidence interval; CSBM, complete spontaneous bowel movement; IBS, irritable bowel syndrome; SE, standard error. Table 1. - Female responders by age and treatment group Placebo Linaclotide 290 μg Placebo Vs Linaclotide 290 μg ≤ 45 Years (N = 396) > 45 Years (N = 401) ≤ 45 Years (N = 396) > 45 Years (N = 400) ≤ 45 Years > 45 Years n (%) P-value n (%) P-value P-value Parameter APC + 1 respondera 59 (14.9) 74 (18.5) 0.1787 123 (31.1) 139 (34.8) 0.2684 < 0.001 < 0.001 30% improvement in abdominal pain for 50% of weeks responder 124 (31.3) 143 (35.7) 0.1938 183 (46.2) 200 (50.0) 0.2852 < 0.001 < 0.001 Adequate relief of IBS symptoms for 50% of weeks responder 112 (28.3) 148 (36.9) 0.0095 197 (49.7) 236 (59.0) 0.0088 < 0.001 < 0.001 Degree of relief of IBS symptoms overall responder 61 (20.7)b 60 (23.8)c 0.3910 133 (44.9)d 121 (45.5)e 0.8948 < 0.001 < 0.001 aAPC +1 responder is defined as a patient who has an increase from baseline of at least 1 in the respective CSBM weekly rate and has a decrease from baseline of at least 30% in the respective weekly abdominal pain score; Some patient data were not captured: bn = 102 responses missing; cn = 149 responses missing; dn = 100 responses missing; en = 134 responses missing. APC, abdominal pain and constipation; CSBM, complete spontaneous bowel movement; IBS, irritable bowel syndrome.