Linaclotide binds to the guanylate cyclase-C receptor on the luminal surface of the intestinal epithelium resulting in increased concentrations of both extra- and intra-cellular cyclic guanosine monophosphate (c-GMP).1
Extracellular c-GMP decreases pain fibre activity thereby reducing visceral pain in animal models, while intracellular c-GMP causes secretion of chloride and bicarbonate into the intestinal lumen leading to increased intestinal fluid and accelerated transit.1
The efficacy and safety of linaclotide for the treatment of IBS-C was investigated in two randomised, double-blind, placebo-controlled phase III studies of similar design: study 1 (n=804) assessed patients over 26 weeks and study 2 (n=800) evaluated patients over 12 weeks before re-randomisation for an additional 4-week treatment period. In both studies, patients received linaclotide 290 microgram or placebo.1-3
Patients met Rome II criteria for IBS-C and were required to report a mean abdominal pain score of 3 or more on a 0–10 point numeric rating scale (criteria that correspond to a moderate to severe IBS population), <3 complete spontaneous bowel movements (SBMs and ≤5 SBMs per week during a 2-week baseline period.1
Investigators used IBS degree of relief response rate (considerably or completely relieved for ≥50% of treatment period) and abdominal pain/discomfort response rate (improvement of ≥30% for at least 50% of the treatment period) at 12 weeks as the co-primary endpoints.1
Pre-treatment, patients had a mean abdominal pain score of 5.6 and bloating score of 6.6 (0-10 scale) with 2.2% of days free of abdominal pain and an average of 1.8 SBMs per week.1
Reduction in IBS relief and abdominal pain/discomfort
In study 1, the IBS degree of relief response rate at 12 weeks was 33.7% in patients treated with linaclotide compared with 13.9% in patients on placebo (p<0.0001), and a further 48.9% of patients showed response to abdominal pain/discomfort comapred with 34.5% in the placebo arm.2
In study 2, patients treated with linaclotide had a IBS degree of relief response rate at week 12 of 33.6% versus 21% for patients on placebo (p<0.0001), and a greater percentage of patients given linaclotide showed a response in terms of abdominal pain/discomfort (50.1% vs 37.5% for placebo, p=0.0003).3
At 26 weeks in study 1, significantly higher percentages of linaclotide-treated patients showed a response in terms of IBS relief and abdominal pain/discomfort compared with patients on placebo: 37% and 54% for linaclotide and 17% and 36% for placebo, respectively (p<0.0001 for both comparisons).4
Other signs and symptoms of IBS-C including bloating, frequency of complete SBMs, straining and stool consistency were improved in linaclotide treated patients compared with those on placebo (p<0.0001). These effects were seen at 1 week and sustained over the entire treatment period.1
The most commonly reported adverse effect in both trials was diarrhoea. This resulted in discontinuation of linaclotide in 4.5% of linaclotide-treated patients compared with 0.2% of patients treated with placebo in study 1. Similar rates of discontinuation were observed in study 2: 5.7% for linaclotide versus 0.3% for placebo.2,3
Prescribers should advise patients to seek medical attention if diarrhoea is severe or prolonged (lasting over 1 week) and temporary discontinuation should be considered in this event.1
- Constella Summary of Product Characteristics, November 2012.
- Chey WD et al. Am J Gastroenterol 2012; 101: 1702–12.
- Rao S et al. Am J Gastroenterol 2012; 107: 1714–1724.
- Quigley EM et al. Aliment Pharmacol Ther 2013; 37: 49–61.
Further information: Almirall