Linaclotide

Abstract: Background There has been no definitive systematic review and meta-analysis to date examining the effect of laxatives and pharmacological therapies in chronic idiopathic constipation (CIC). Objective To assess efficacy of these therapies systematically in CIC. Design Systematic review and meta-analysis of randomised controlled trials (RCTs). Data sources MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (up to September 2010). Eligibility criteria for selecting studies Placebocontrolled trials of laxatives or pharmacological therapies in adult CIC patients were eligible. Minimum duration of therapy was 1 week. Trials had to report either a dichotomous assessment of overall response to therapy at last point of follow-up in the trial, or mean number of stools per week during therapy. Study appraisal and synthesis methods Symptom data were pooled using a random effects model. Effect of laxatives or pharmacological therapies compared to placebo was reported as RR of failure to respond to therapy, or a weighted mean difference (WMD) in mean number of stools per week, with 95% CIs. Results Twenty-one eligible RCTs were identified. Laxatives (seven RCTs, 1411 patients, RR¼0.52; 95% CI 0.46 to 0.60), prucalopride (seven trials, 2639 patients, RR¼0.82; 95% CI 0.76 to 0.88), lubiprostone (three RCTs, 610 patients, RR¼0.67; 95% CI 0.56 to 0.80), and linaclotide (three trials, 1582 patients, RR¼0.84; 95% CI 0.80 to 0.87) were all superior to placebo in terms of a reduction in risk of failure with therapy. Treatment effect remained similar when only RCTs at low risk of bias were included in the analysis. Diarrhoea was significantly more common with all therapies. Limitations Only two RCTs were conducted in primary care, and total adverse events data for laxatives and linaclotide were sparse. Conclusions Laxatives, prucalopride, lubiprostone and linaclotide are all more effective than placebo for the treatment of CIC.

Abstract: Background Linaclotide 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. Methods We 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. Results For 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<0.0...

Abstract: Objective: We aimed to determine the efficacy, impact on quality of life (QOL), and safety of prucalopride, a selective, high-affinity 5-HT4 receptor agonist, in patients with chronic constipation (CC). Methods: In this multi-centre, randomized, placebo-controlled, parallel-group, phase III study, patients with CC (≤2 spontaneous complete bowel movements ([SCBM]/week) received 2 or 4 mg prucalopride or placebo, once daily, for 12 weeks. The primary efficacy endpoint was the proportion of patients reaching ≥3 SCBM/week. The key secondary efficacy endpoint was the proportion of patients having an increase of ≥1 SCBM/week. The primary QOL endpoint was the Patient Assessment of Constipation (PAC)-QOL satisfaction subscale score. Safety parameters included adverse events, laboratory values, and cardiovascular events. Results: Efficacy was evaluated over 713 patients. Averaged over 12 weeks, higher proportions of patients on prucalopride 2 mg (19.5%; p Conclusion: Prucalopride significantly and consistently improved bowel function, associated symptoms and satisfaction in chronically constipated patients.