Linaclotide Found to Reduce Unpleasant Effects of Chronic Constipation

In 2 placebo-controlled phase 3 trials, a 12-week daily regimen of linaclotide significantly reduced symptoms of chronic constipation and improved quality of life. Study investigators said the ameliorating effects of linaclotide were evident within 24 hours of the initial dose and persisted throughout the trials [N Engl J Med. 2011;365(6):527-536]. Diarrhea was the most common treatment-related adverse event and caused some patients to discontinue therapy, but its severity was generally mild to moderate and most patients indicated a desire to keep taking linaclotide at the study’s conclusion. Trial 303 and Trial 01 were conducted from mid-August 2008 to mid-August 2009 at centers throughout the United States and Canada. The only difference in protocol between the randomized, double-blind studies was a 4-week withdrawal period that followed treatment for Trial 303 participants. Adults eligible for the study were required to have chronic constipation, described as fewer than 3 spontaneous bowel movements (SBMs) per week and straining during evacuation, lumpy or hard stools, or a sensation of incomplete evacuation or any combination of these criteria for at least one-quarter of weekly bowel movements for 12 weeks in the past year. For 2 weeks prior to the study’s start date, the men and women were told not to take any anticholinergic agents or narcotics; nor were they to use laxatives in the 24 hours prior to trial inception. During this time, participants reported daily constipation symptoms and bowel habits. Those having fewer than 6 SBMs per week, of which no more than 3 were complete spontaneous bowel movements (CSBMs), could continue with the study. The 1276 participants were randomized to receive 145 mcg of linaclotide, 290 mcg of linaclotide, or placebo once a day for 12 weeks. During this time, they were requested to avoid major lifestyle changes, such as a new diet or exercise regimen. At baseline and at 12 weeks, participants completed the Patient Assessment of Constipation Quality of Life (PAC-QOL) instrument. Each day, they used an interactive voice-response system to document the number of SBMs and CSBMs; rescue medications used; stool consistency; and any straining, abdominal discomfort, and bloating. They also assessed constipation severity and relief each week. The primary end point for the studies consisted of 3 or more CSBMs per week, with 1 or more additional CSBMs each week compared with baseline levels, for a minimum of 9 weeks. In Trial 303, 21.2% of patients taking 145 mcg of linaclotide and 19.4% of those given 290 mcg of linaclotide met these criteria, as did 16.0% of patients in the 145-mcg linaclotide arm and 21.3% in the 290-mcg linaclotide arm of Trial 01. Significantly smaller proportions of patients in the placebo arms of Trial 303 and Trial 01 met the primary end point (3.3% vs 6.0%, respectively). For each week of the study, the 2 linaclotide doses demonstrated an efficacy advantage over placebo in both studies. Overall, the linaclotide groups also demonstrated significant improvement from baseline in bowel and abdominal symptoms, severity of constipation, and PAC-QOL scores compared with the control groups. Patients randomized to linaclotide expressed greater satisfaction with treatment than did those taking placebo. Linaclotide, a peptide agonist of the guanylate cyclase C receptor, works in part by increasing luminal fluid, thereby accelerating intestinal transit. The authors said this likely accounted for the higher prevalence of diarrhea among linaclotide-treated patients, accounting for 4.2% of discontinuations in this cohort versus 0.5% of discontinuations in the placebo cohort. Although findings suggest “linaclotide has the potential to offer multisymptom relief to patients with chronic constipation,” the authors said studies are needed to evaluate linaclotide’s long-term safety profile.