Overview

The content of this evidence summary was up-to-date in April 2013. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Key points from the evidence

Linaclotide (Constella) is a first-in-class, oral, once-daily guanylate cyclase-C receptor agonist (GCCA), licensed for the symptomatic treatment of moderate-to-severe irritable bowel syndrome with constipation (IBS-C) in adults. It received a European marketing authorisation in November 2012 and is expected to be launched during the first half of 2013.

Linaclotide has been evaluated in 2 double-blind, randomised, placebo-controlled trials of patients with IBS-C (Rao et al. 2012 [Trial 1] and Chey et al. 2012 [Trial 2]). An analysis of both trials, presenting the pre-specified analysis of primary efficacy end points as required by the European Medicines Agency (EMA), was also published in 2013 (Quigley et al. 2013). In both trials, a statistically greater proportion of linaclotide-treated patients, compared with placebo-treated patients, met the 2 co-primary efficacy end points required by the EMA, which were '12-week abdominal pain/discomfort responders' (trial 1: 54.8% compared with 41.8%; trial 2: 54.1% compared with 38.5%; p<0.001) and 'IBS degree-of-relief responders' (trial 1: 37.0% compared with 18.5%; trial 2: 39.4% compared with 16.6%; p<0.0001). A significantly greater percentage of patients treated with linaclotide also met the composite primary end point required by the US Food and Drug Administration (FDA) of 'improvement of ≥30% in average daily worst abdominal pain score and increase by ≥1 complete spontaneous bowel movement (CSBM) from baseline for ≥50% of the weeks assessed' (trial 1: 33.6% [linaclotide] compared with 21.0% [placebo]; trial 2: 33.7% [linaclotide] compared with 13.9% [placebo]; in both trials p<0.001 and number needed to treat [NNT] was 5 and 8). A statistically greater number of patients treated with linaclotide also met the 3 additional efficacy end points required by the FDA compared with the placebo-treated patients (p<0.05). The most common treatment-related adverse event was diarrhoea.

The NICE clinical guideline Irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care (NICE clinical guideline 61) was published in 2008. It identifies self-help as a key component of the management of IBS, and advises that people should receive information on general lifestyle, physical activity and diet. Based on the nature and severity of symptoms, pharmacological management may be considered, with the choice of agent(s) depending on the predominant symptom(s). Treatments include antispasmodic agents for abdominal pain, and laxatives or antimotility agents, depending on the presence of constipation or diarrhoea. Off-label use of a tricyclic antidepressant (TCA) or a selective serotonin reuptake inhibitor (SSRI) may be considered for people whose condition does not respond to first-line treatments.

Local decision makers will need to consider the place of linaclotide alongside existing treatments that may be used to manage symptoms of IBS-C, such as the concomitant use of antispasmodics and laxatives. The publication of head-to-head studies against existing treatments would facilitate a better understanding of its place in the management of IBS-C.

Key evidence

Trial 1: Rao S, Lembo AJ, Shiff SJ et al. (2012) 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. American Journal of Gastroenterology 107: 1714–24

Trial 2: Chey WD, Lembo AJ, Lavins BJ et al. (2012) Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. American Journal of Gastroenterology 107: 1702–12

Trial 1 and 2 – analysis of EMA co-primary end points: Quigley EM, Tack J, Chey WD et al. (2013) Randomised clinical trials: linaclotide phase 3 studies in IBS-C – a prespecified further analysis based on European Medicines Agency-specified endpoints. Alimentary Pharmacology and Therapeutics 37: 49–61

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.