Effects of Linaclotide on Abdominal and Bowel Symptoms Over the First Seven Days of Treatment in Patients with Irritable Bowel Syndrome with Constipation

Abstract

Purpose: To assess changes from baseline in abdominal and bowel symptoms in patients with irritable bowel syndrome with constipation (IBS-C) over the first seven days of treatment with linaclotide (LIN), an investigational, minimally absorbed guanylate cyclase-C agonist (GCCA). Methods: Patients meeting modified Rome II criteria for IBS-C were randomized to oral once-daily 290 μg LIN or placebo (PBO) in two Phase three trials. Using pooled data from the first seven days of the Treatment Period, the following were determined: mean daily percent change from baseline in abdominal symptoms for patient sub-populations with baseline score ≥3 for each symptom parameter (pain, discomfort, bloating, cramping, fullness) rated on an 11-point scale (0-10), and mean daily change from baseline for stool consistency (Bristol Stool Form Scale: 1=separate hard lumps, like nuts, to 7=watery, no solid pieces, entirely liquid) and straining (5-point ordinal scale [1-5]). The percentages of patients having ≥1 spontaneous bowel movement (SBM) and complete SBM (CSBM) on each of the first seven days of treatment and the mean number of SBMs and CSBMs during the first week of treatment were calculated. Median times to first SBM and CSBM were also calculated using Kaplan-Meier methodology. Results: The pooled intent-to-treat population included 797 PBO and 805 LIN patients. Compared with PBO, LIN statistically significantly improved abdominal bloating and fullness on day one, pain and discomfort by day two, and cramping by day three (Table 1). The percentages of patients reporting ≥1 SBM or CSBM were statistically significantly higher for LIN vs PBO on each of the initial seven days of treatment (Table 2). Approximately 50% and 20% of LIN patients had an SBM and CSBM, respectively, on day one vs 20% and 6% of PBO patients (Table 2). Likewise, LIN statistically significantly improved stool consistency and straining by day 1 compared with PBO (P<.0001 for both, data not shown). The median time to the first SBM was two days for LIN and PBO patients; the median time to the first CSBM was five days for LIN patients and 20 days for PBO patients (P <.0001). LIN patients reported an average of 6.6 SBMs and 2.4 CSBMs during week one compared with 3.5 and 0.9 for PBO patients, respectively (P<.0001). Diarrhea incidence during the first seven days of treatment was 10% (n=80) and 0.4% (n=3) for LIN and PBO patients, respectively.Table: [1747] Table 1. Mean Percent Improvement in Abdominal Symptoms, Days 1-7Table: [1747] Table 2. Percentage of Patients with ≥1 SBM or CSBM for Each of Days 1-7Conclusion: Compared with PBO, LIN was associated with statistically significantly greater improvement in all measured bowel symptoms by day one and abdominal symptoms by day three, which continued to progressively increase through the first week of treatment. Disclosure: Lin Chang: Consultant (Advisory Board) for Ironwood Pharmaceuticals, Inc., and Forest Laboratories, Inc.; Anthony J. Lembo, Consultant for Ironwood Pharmaceuticals, Inc.; Steven Shiff, Harvey Schneier, and Kelvin Shi: employees of Forest Laboratories, Inc., in which they own stock and/or stock options. Bernard J. Lavins: employee of Ironwood Pharmaceuticals, Inc., in which he owns stock and/or stock options, and is a stock shareholder in J&J Health Care Companies; James Shao, Mark Currie, and Jeffrey Johnston: employees of Ironwood Pharmaceuticals, Inc., in which they own stock and/or stock options. 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.