Linaclotide was associated with significant improvement in symptoms of irritable bowel syndrome with constipation, including abdominal pain, within 1 week of starting therapy, Dr. Jeffrey M. Johnston and colleagues reported in the December issue of Gastroenterology.
However, diarrhea was a common side effect, leading to study withdrawal by more than a dozen patients.
Linaclotide is a novel, 14–amino acid peptide that binds to guanylate cyclase-C receptors on intestinal enterocytes, wrote Dr. Johnston, who is employed by the drug’s manufacturer, Ironwood Pharmaceuticals Inc.
In animal models, it has been shown to increase fluid secretion and transit, he added.
In the current study, Dr. Johnston and colleagues randomized 420 patients in a double-blind, placebo-controlled, phase IIB study. All patients were aged 18 years or older and met the Rome II criteria for irritable bowel syndrome (IBS). The mean patient age was 44 years, and 92% were female (Gastroenterology 2010 December [doi:10.1053/j.gastro.2010.08.041]).
All participants also reported having fewer than three spontaneous bowel movements per week, and at least one of the following symptoms occurring with 25% or more of their bowel movements: straining, lumpy or hard stools, or a sensation of incomplete evacuation.
Patients were randomized into five groups. One received a daily placebo, and the rest received once-daily linaclotide in doses of 75 mcg, 150 mcg, 300 mcg, or 600 mcg, taken orally before the first meal of the day.
According to daily assessments that were completed over the phone via an interactive voice-response system, all patients receiving active treatment who completed the study met the primary end point, which was an increase in complete spontaneous bowel movements (CSBMs), measured at 12 weeks, compared with baseline.
At week 12, the group receiving 75 mcg had an increase of 2.90 CSBMs per week; the 150-mcg group increased by 2.49 CSBMs per week; the 300-mcg group had an increase of 3.61 bowel movements per week; and the 600-mcg group increased by 2.68 CSBMs per week over their baseline (P less than or equal to .01 for all doses).
The group receiving placebo, in contrast, had a mean increase of 1.01 CSBM per week.
There were also significant decreases in abdominal pain – which was measured on a 5-point scale, with 1 signifying no pain and 5 being very severe pain – among patients taking linaclotide.
Compared with baseline, by 12 weeks the 75-mcg treatment group reported a mean reduction in the pain scale of 0.71 points, as did the 150-mcg group. The 300-mcg group had a reduction of 0.90 points, and the 600-mcg dosing group had a mean decrease of 0.86 points, compared with 0.49 points for placebo patients (P less than or equal to .05 for all doses).
Moreover, linaclotide’s effects "occurred within the first week of therapy and were sustained for the entire 3-month duration of this study," wrote the investigators.
The treatment was not without side effects. According to the researchers, the most frequent of these was diarrhea. They noted that the diarrhea was dose dependent, reported by 11.4%, 12.2%, 16.5%, and 18.0% of patients in the 75-, 150-, 300-, and 600-mcg dose groups, respectively, compared with 1.2% in the placebo group. "No dehydration, electrolyte changes, or other adverse clinical sequelae from diarrhea were reported," the authors wrote.
"Linaclotide resulted in sustained effects in the treatment of a common condition for which few therapies are currently available," concluded Dr. Johnston and associates.
The results of this placebo-controlled, dose-range–finding, phase IIB study "support further development of linaclotide for treatment of adults with [IBS constipation]".
Several of Dr. Johnston’s coinvestigators are also employees of linaclotide’s manufacturer, Ironwood Pharmaceuticals Inc., which also funded the study.