Correlation of Global Assessments with Symptom Endpoints in Phase 3 Clinical Trials of Linaclotide in Chronic Constipation

Abstract

Purpose: Linaclotide is a first-in-class, minimally-absorbed guanylate cyclase-C receptor agonist that statistically significantly improved bowel and abdominal symptoms, and patient global assessments in two recent Phase 3 chronic constipation (CC) trials. Both trials featured patient-reported global assessments - multidimensional endpoints that have been shown to integrate individual bowel and abdominal symptom endpoints and are useful overall measures of treatment efficacy in CC clinical trials. Here, we evaluate the correlation of 3 patient-reported global endpoints with the primary and secondary symptom-based endpoints. Methods: Two placebo-controlled Phase 3 trials evaluated the effects of 133 and 266 μg linaclotide administered orally once daily for 12 weeks to 1272 adults meeting modified Rome II CC criteria. Bowel symptoms (stool consistency, straining, completeness of evacuation for each spontaneous bowel movement [SBM]), abdominal symptoms (daily abdominal discomfort, bloating), weekly constipation severity, and global relief of constipation symptoms were assessed using an interactive voice response system. Treatment satisfaction was collected at multiple timepoints during the treatment period. A post-hoc analysis of the correlation of key efficacy endpoints with the global assessments was performed. Results: Both linaclotide doses demonstrated a statistically significant treatment effect for all endpoints, including bowel and abdominal symptoms, global relief, and treatment satisfaction. Weekly global relief and constipation severity correlated well with improvement in bowel habits (r-values 0.51-0.60) and abdominal symptoms (0.46-0.59). Treatment satisfaction also showed good correlation with bowel (0.44-0.59) and abdominal (0.43-0.48) symptom improvement.[1304] Table. Spearman correlations of global parameters with Key CC symptoms*Conclusion: In both Phase 3 clinical trials, linaclotide 133 and 266 μg demonstrated statistically significant treatment effects on CC bowel and abdominal symptoms and global assessments. All 3 global assessments were correlated with bowel and abdominal symptoms, with strongest correlations occurring for weekly assessments. Disclosure: A. Lembo - Paid Consultant: Ironwood Pharmaceuticals. H. Schneier, S. Shiff, and D. Jia - Employees: Forest Research Institute and owner of stock/stock options in Forest Labs. B. Lavins, J. MacDougall, C. Kurtz, M. Currie, and J. Johnston - Employees of and owners of stock/stock options in Ironwood Pharmaceuticals. Disclosure: Funded by Ironwood Pharmaceuticals and Forest Laboratories.