Linaclotide Improves Abdominal Symptoms Over Placebo in Patients With Chronic Idiopathic Constipation: A Pooled Analysis

Introduction: Patients with chronic idiopathic constipation (CIC) based on Rome criteria may experience abdominal symptoms of pain, discomfort, or bloating. Understanding the impact of linaclotide (LIN) on bothersome abdominal symptoms helps healthcare professionals improve management. This post hoc analysis evaluated the efficacy of LIN on abdominal symptoms in patients with CIC. Methods: Data from patients meeting modified Rome II/III criteria for CIC were pooled for LIN 145 µg and placebo (PBO) arms from 4 Phase 3 LIN-CIC studies (NCT00730015, NCT00765882, NCT02291679, and NCT01642914). Patients reported daily severity ratings of abdominal pain, discomfort, and bloating on a 5- or 11-point scale (11-point scale standardized to 5 points prior to pooling). Outcome measures of change from baseline (CFB) at week 12, CFB per week, %CFB at week 12, and percent of patients meeting responder criteria (≥9 weeks with symptom rating improvement CFB ≥1) at week 12 were calculated for these symptoms. Analysis of covariance models were used to compute within-group and between-group change in average symptom scores including treatment arm and geographic region as factors and baseline values as a covariate. Pairwise comparisons to PBO were adjusted for these factors and the covariate, with nominal P-values < 0.05 considered significant. The difference in responder rate between LIN and PBO was calculated using the Cochran–Mantel–Haenszel test. Results: Of the 1,992 patients (994 LIN, 998 PBO) included in this study, similar demographic and baseline characteristics were identified between groups (Table 1). At 12 weeks, the LIN group had statistically significant decreases in CFB and %CFB for abdominal pain, discomfort, and bloating compared to PBO (all P< 0.0001) [Figure 1A-B]. Significant improvements in all 3 abdominal symptoms with LIN vs PBO were seen starting at week 1 and sustained through week 12 (Figure 1C). A significantly greater proportion of patients in the LIN group were responders for improvements in abdominal pain, discomfort and bloating vs the PBO group (all P≤0.001) [Figure 1D]. Conclusion: In this pooled post hoc analysis of nearly 2,000 patients with CIC and abdominal symptoms not meeting the criteria for irritable bowel syndrome with constipation, LIN demonstrated significantly greater improvement vs PBO in the abdominal symptoms of pain, discomfort, and bloating. Symptom relief occurred as early as week 1 and was sustained throughout the entire treatment period.Figure 1.: Change From Baseline in Abdominal Pain, Discomfort, and Bloating in Patients With Chronic Idiopathic Constipation Treated with Linaclotide 145 µg Vs Placebo At 12 Weeks (A), Percent Change (B), And Per Week (C); Proportion Of Responders At 12 Weeks For These Symptoms (D). Table 1. - Baseline demographics, characteristics, and disease severity PlaceboN = 1998 Linaclotide 145 μgN = 994 TotalN = 1992 Patient Demographics Age, mean (SD) 46.7 (14.2) 47.5 (13.5) 47.1 (13.9) Female, n (%) 853 (85.5) 838 (84.3) 1691 (84.9) Race, n (%) White 724 (72.5) 723 (72.7) 1447 (72.6) Black or African American 237 (23.7) 235 (23.6) 472 (23.7) Asian 24 (2.4) 20 (2) 44 (2.2) American Indian or Alaska Native 1 (0.1) 5 (0.5) 6 (0.3) Native Hawaiian or Other Pacific Islander 1 (0.1) 0 1 (0.1) Multiple 3 (0.3) 4 (0.4) 7 (0.4) Other 8 (0.8) 7 (0.7) 15 (0.8) Hispanic or Latino, n (%) 237 (23.7) 236 (23.7) 473 (23.7) Baseline Characteristics Weight, kg, mean (SD) 78.46 (19.0) 78.11 (18.1) 78.28 (18.6) BMI, kg/m2, mean (SD) 28.74 (6.4) 28.64 (6.1) 28.69 (6.2) Disease Severity at Baseline Abdominal pain score, mean (SD) 2.51 (1.0) 2.48 (1.0) 2.50 (1.0) Abdominal discomfort score, mean (SD) 2.86 (1.0) 2.79 (1.0) 2.82 (1.0) Bloating score, mean (SD) 3.08 (0.9) 3.05 (0.9) 3.07 (0.9) SD, standard deviation.