Effects of Linaclotide on Bowel Movements (BMs) and Straining in Patients with Chronic Constipation (CC): A Post Hoc Analysis of Pooled Data from Two Phase Three Trials (2012)

Purpose: To assess (1) the effects of linaclotide, an investigational, minimally absorbed guanylate cyclase-C agonist (GCCA), compared to placebo on the distribution of BMs occurring with the use of rescue medications (rBMs), spontaneous BMs (SBMs), and complete SBMs (CSBMs) and; (2) the effects of linaclotide versus rescue medication on straining associated with SBMs in CC patients. Methods: Pooled data from two Phase three placebo-controlled trials in patients with CC who had an average of <3 CSBMs/week and ≤6 SBMs/week during a 2-week Pretreatment Period, were used in this post hoc analysis. SBMs were BMs that occurred in the absence of rescue medication (ie, laxative, suppository, or enema use on the day before the BM or on the day of the BM). CSBMs were SBMs accompanied by a patient-reported feeling of complete evacuation. For each patient, BMs were categorized as follows: CSBMs, SBMs that were not CSBMs, and rBMs (ie, BMs after rescue medication use). Straining associated with each BM was assessed on a 5-point scale: 1=Not at all, 2=A little bit, 3=A moderate amount, 4=A great deal, 5=An extreme amount. Results: The pooled intent-to-treat population included 423 placebo patients, 430 linaclotide 145 μg patients, and 418 linaclotide 290 μg patients. Linaclotide statistically significantly increased SBM and CSBM rates compared to placebo, but not the rBM rate. Linaclotide also increased the proportion of BMs that were CSBMs compared to placebo and compared to the baseline distribution (Figure 1). The distribution of straining for BMs occurring with either rescue medication use or linaclotide 145 or 290 μg during the Pretreatment and Treatment Periods is shown in Table 1. Use of rescue medication or linaclotide resulted in decreased straining compared to baseline (Table 1); however, more linaclotide-treated patients (both doses) had either little or no straining with SBMs compared to placebo patients who took rescue medications for straining with rBMs (Table 1).Figure 1: BM Distribution.Table 1: Effects of Linaclotide vs Rescue Medication on Straining During BMsaConclusion: Patients who received linaclotide compared to placebo had a significant increase in overall BMs, particularly a shift towards CSBMs, and decreased straining, reflecting improvement in bowel habits. Linaclotide patients also reported less straining associated with BMs than did patients treated with placebo who received rescue medications. Disclosure: Satish Rao: Consultant for Forest Laboratories, Inc., and Ironwood Pharmaceuticals, Inc., and serves on Advisory Committees or Review Panels for Forest Laboratories, Inc.; Anthony Lembo: Consultant for Ironwood Pharmaceuticals, Inc.; Bernard J Lavins: employee of Ironwood Pharmaceuticals, Inc., and Stock Shareholder J&J Health Care Companies; Brenda Jeglinski, Donald Fitch, James MacDougall, Mark Currie, and Jeffrey Johnston: employees of Ironwood Pharmaceuticals, Inc., in which they own stock and/or stock options; Steven Shiff, Susan Fox, Kelvin Shi, and Harvey Schneier: employees of Forest Laboratories, Inc.; Steven Shiff and Harvey Schneier own stock options and shares in Forest Laboratories. This research was supported by an industry grant. Forest Laboratories, Inc., and Ironwood Pharmaceuticals, Inc., were involved in the study design; collection, analysis and data interpretation; and decision to submit these data for presentation. Study was sponsored by Forest Laboratories, Inc., and Ironwood Pharmaceuticals, Inc.