Steven J. Shiff

Linaclotide for Irritable Bowel Syndrome With Constipation: A 26-Week, Randomized, Double-blind, Placebo-Controlled Trial to Evaluate Efficacy and Safety

OBJECTIVES:Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide treatment in patients with irritable bowel syndrome with constipation (IBS-C) over 26 weeks.METHODS:This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290u2009μg of oral linaclotide once daily for a 26-week treatment period. The primary and the secondary efficacy assessments were evaluated over the first 12 weeks of treatment. Primary end points included the Food and Drug Administrations (FDAs) end point for IBS-C (responder: a patient who reported (i) improvement of ≥30% from baseline in average daily worst abdominal pain score and (ii) increase of ≥1 complete spontaneous bowel movement (CSBM) from baseline, both in the same week for ≥6/12 weeks) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.RESULTS:In all, 804 patients (mean age=44 years, female=90%, white=78%) were evaluated; 33.7% of linaclotide-treated patients were FDA end point responders, vs. 13.9% of placebo-treated patients (P<0.0001) (number needed to treat=5.1, 95% confidence interval (CI): 3.9, 7.1). The pain responder criterion of the FDA end point was met by 48.9% of linaclotide-treated patients vs. 34.5% of placebo-treated patients (number needed to treat=7.0, 95% CI: 4.7, 13.1), and the CSBM responder criterion was met by 47.6% of linaclotide-treated patients, vs. 22.6% of placebo patients (number needed to treat=4.0, 95% CI: 3.2, 5.4). Remaining primary end points (P<0.0001) and all secondary end points (P<0.001), including abdominal pain, abdominal bloating, and bowel symptoms (SBM and CSBM rates, Bristol Stool Form Scale (BSFS) score, and straining), were also statistically significantly improved with linaclotide vs. placebo. Statistically significant differences from placebo were observed for responder and continuous end points over 26 weeks of treatment. AE incidence was similar between treatment groups, except for diarrhea, which caused discontinuation in 4.5% of linaclotide patients vs. 0.2% of placebo patients.CONCLUSIONS:Linaclotide 290u2009μg once daily significantly improved abdominal and bowel symptoms associated with IBS-C over 26 weeks of treatment.

A 12-Week, Randomized, Controlled Trial With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome With Constipation

OBJECTIVES:Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C).METHODS:This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290u2009μg oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administrations (FDAs) primary end point for IBS-C (responder: improvement of ≥30% in average daily worst abdominal pain score and increase by ≥1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50% of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.RESULTS:The trial evaluated 800 patients (mean age=43.5 years, female=90.5%, white=76.9%). The FDA end point was met by 136/405 linaclotide-treated patients (33.6%), compared with 83/395 placebo-treated patients (21.0%) (P<0.0001) (number needed to treat: 8.0, 95% confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6/12 treatment period weeks, a reduction of ≥30% in abdominal pain (50.1 vs. 37.5%, P=0.0003) and an increase of ≥1 CSBM from baseline (48.6 vs. 29.6%, P<0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points (P<0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points (P<0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7% of linaclotide and 0.3% of placebo patients.CONCLUSIONS:Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.

Two Randomized Trials of Linaclotide for Chronic Constipation

BACKGROUNDnLinaclotide is a minimally absorbed peptide agonist of the guanylate cyclase C receptor. In two trials, we aimed to determine the efficacy and safety of linaclotide in patients with chronic constipation.nnnMETHODSnWe conducted two randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials (Trials 303 and 01) involving 1276 patients with chronic constipation. Patients received either placebo or linaclotide, 145 μg or 290 μg, once daily for 12 weeks. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. Adverse events were also monitored.nnnRESULTSnFor Trials 303 and 01, respectively, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 μg of linaclotide and by 19.4% and 21.3% of the patients who received 290 μg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide with placebo). Improvements in all secondary end points were significantly greater in both linaclotide groups than in the placebo groups. The incidence of adverse events was similar among all study groups, with the exception of diarrhea, which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups.nnnCONCLUSIONSnIn these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation. Additional studies are needed to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation. (Funded by Ironwood Pharmaceuticals and Forest Research Institute; ClinicalTrials.gov numbers, NCT00765882 and NCT00730015.).

Randomised clinical trials: linaclotide phase 3 studies in IBS‐C – a prespecified further analysis based on European Medicines Agency‐specified endpoints

Treatment options that improve overall symptoms of irritable bowel syndrome with constipation (IBS‐C) are lacking.

Effect of Linaclotide on Severe Abdominal Symptoms in Patients With Irritable Bowel Syndrome With Constipation

BACKGROUND & AIMSnPatients with irritable bowel syndrome with constipation (IBS-C) have abdominal symptoms that vary in severity. Linaclotide, a guanylate cyclase-C agonist, improves abdominal and bowel symptoms in these patients. We examined the prevalence of severe abdominal symptoms in patients with IBS-C and assessed the effects of linaclotide on abdominal symptoms, global measures, and quality of life (QOL).nnnMETHODSnIn two phase 3 trials, patients who met modified Rome II criteria for IBS-C were randomly assigned to groups given oral, once-daily linaclotide (290 μg) or placebo for 12 weeks. During the baseline (2 weeks prior to treatment) and treatment periods, patients rated abdominal pain, discomfort, bloating, fullness, and cramping daily (from 0 = none to 10 = very severe). Linaclotides effects on abdominal symptoms, global measures, and IBS-related QOL were assessed in subpopulations of patients who rated specific individual abdominal symptoms as severe (≥ 7.0) at baseline.nnnRESULTSnIn the intent-to-treat population (1602 patients; 797 receiving placebo and 805 receiving linaclotide), baseline prevalence values for severe abdominal symptoms were 44% for bloating, 44% for fullness, 32% for discomfort, 23% for pain, and 22% for cramping, with considerable overlap among symptoms. In patients with severe symptoms, linaclotide reduced all abdominal symptoms; mean changes from baseline severity scores ranged from -2.7 to -3.4 for linaclotide vs -1.4 to -1.9 for placebo (P < .0001). Linaclotide improved global measures (P < .0001) and IBS-QOL scores (P < .01) compared with placebo. Diarrhea was the most common adverse event of linaclotide in patients with severe abdominal symptoms (18.8%-21.0%).nnnCONCLUSIONSnOf 5 severe abdominal symptoms assessed, bloating and fullness were most prevalent in patients with IBS-C. Linaclotide significantly improved all abdominal symptoms, global measures, and IBS-QOL in subpopulations of IBS-C patients with severe abdominal symptoms. Clinicaltrials.govnnnNUMBERSnNCT00938717, NCT00948818.

Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial.

Background Abdominal bloating is a common and bothersome symptom of chronic idiopathic constipation. The objective of this trial was to evaluate the efficacy and safety of linaclotide in patients with chronic idiopathic constipation and concomitant moderate-to-severe abdominal bloating. Methods This Phase 3b, randomized, double-blind, placebo-controlled clinical trial randomized patients to oral linaclotide (145 or 290 μg) or placebo once daily for 12 weeks. Eligible patients met Rome II criteria for chronic constipation upon entry with an average abdominal bloating score ≥5 (self-assessment: 0 10-point numerical rating scale) during the 14-day baseline period. Patients reported abdominal symptoms (including bloating) and bowel symptoms daily; adverse events were monitored. The primary responder endpoint required patients to have ≥3 complete spontaneous bowel movements/week with an increase of ≥1 from baseline, for ≥9 of 12 weeks. The primary endpoint compared linaclotide 145 μg vs. placebo. Results The intent-to-treat population included 483 patients (mean age=47.3 years, female=91.5%, white=67.7%). The primary endpoint was met by 15.7% of linaclotide 145 μg patients vs. 7.6% of placebo patients (P<0.05). Both linaclotide doses significantly improved abdominal bloating vs. placebo (P<0.05 for all secondary endpoints, controlling for multiplicity). Approximately one-third of linaclotide patients (each group) had ≥50% mean decrease from baseline in abdominal bloating vs. 18% of placebo patients (P<0.01). Diarrhea was reported in 6% and 17% of linaclotide 145 and 290 μg patients, respectively, and 2% of placebo patients. AEs resulted in premature discontinuation of 5% and 9% of linaclotide 145 μg and 290 μg patients, respectively, and 6% of placebo patients. Conclusions Once-daily linaclotide (145 and 290 μg) significantly improved bowel and abdominal symptoms in chronic idiopathic constipation patients with moderate-to-severe baseline abdominal bloating; in particular, linaclotide significantly improved abdominal bloating compared to placebo, an important finding given the lack of agents available to treat abdominal bloating in chronic idiopathic constipation patients. Trial Registration ClinicalTrials.gov NCT01642914

The impact of abdominal pain on global measures in patients with chronic idiopathic constipation, before and after treatment with linaclotide: a pooled analysis of two randomised, double-blind, placebo-controlled, phase 3 trials

Few clinical trials in chronic idiopathic constipation (CIC) patients have evaluated abdominal symptom severity and whether CIC patients with abdominal symptoms respond similarly to patients with limited abdominal symptoms.

An evaluation of the FDA Responder Endpoint for IBS‐C clinical trials: analysis of data from linaclotide Phase 3 clinical trials

Our objective was to evaluate the performance of the Food and Drug Administration (FDA) Responder Endpoint for clinical trials in IBS‐C, using data from two large Phase 3 clinical trials of linaclotide. The FDA interim endpoint requires that, for 50% of trial weeks, patients report ≥30% decrease in Abdominal Pain at its worst and (in the same week) an increase in Complete Spontaneous Bowel Movements (CSBMs) of ≥1 from baseline.

A review of the clinical efficacy of linaclotide in irritable bowel syndrome with constipation

Abstract Objectives: The aims were: firstly, to review the definition and diagnosis of irritable bowel syndrome with constipation (IBS-C, a subtype of IBS); secondly, to critically assess current therapies for IBS-C with a focus on effectiveness for abdominal pain; and thirdly, to review clinical studies evaluating the efficacy of linaclotide, a therapy recently approved by the US Food and Drug Administration for the treatment of adults with IBS-C and chronic idiopathic constipation and the European Medicines Agency for the symptomatic treatment of moderate to severe IBS-C in adults, and in development for treatment of IBS-C worldwide. Methods: A comprehensive literature review was performed to summarize IBS-C and current treatments. MEDLINE and gastrointestinal society congress proceedings were searched to identify data from linaclotide clinical studies in adults with IBS-C published between January 2010 and August 2012. Results: IBS-C patients have chronic, relapsing symptoms. Rome III diagnostic criteria define the presence of chronic abdominal pain that improves with defecation and has onset associated with changes in stool frequency or form as a key element of IBS-C and other IBS subtypes. IBS-C patients generally are not completely satisfied with existing therapies. A therapy that treats bowel and abdominal symptoms effectively and can be taken safely on a chronic basis is a current unmet need for IBS-C patients. The guanylate cyclase-C agonist linaclotide has been shown to reduce visceral hypersensitivity in preclinical studies and to improve abdominal pain and constipation symptoms in phase 2 and 3 clinical trials of IBS-C patients. Conclusions: IBS-C is a functional gastrointestinal disorder with chronic, relapsing abdominal and constipation symptoms. By virtue of its effects in relieving abdominal pain by reducing visceral hypersensitivity and improving constipation symptoms by increasing intestinal secretion and accelerating transit, linaclotide may be uniquely positioned for a role in the management of IBS-C patients.

Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C

Background Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain. Objective The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms. Methods Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed. Results Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48–0.54, 0.32–0.39, and 0.61–0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS-C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%–76% and 71%–82% of weeks with agreement, respectively). Conclusions AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.