BOSTON – The results of two 12-week, randomized, placebo-controlled phase III trials of linaclotide showed that the drug produced significant improvement in key end points related to chronic constipation.

Quality of life self-assessments also showed a favorable response, according to Dr. Anthony J. Lembo, who presented the results of both studies as a poster at Neurogastroenterology and Motility 2010.

At the same meeting, which was hosted by the American Neurogastroenterology and Motility Society, Dr. Jeffrey M. Johnston reported in an oral presentation the results of the 4-week randomized withdrawal period that followed one of the studies. The findings showed that no rebound effects were seen after linaclotide cessation.

Linaclotide is a minimally absorbed, 14-amino-acid peptide, guanylate cyclase-C agonist, said Dr. Lembo, a gastroenterologist at Beth Israel Deaconess Medical Center, Boston. It is produced by Ironwood Pharmaceuticals Inc., which supported the studies. Dr. Johnston is the chief medical officer at Ironwood Pharmaceuticals.

Two phase III trials were conducted, one with an intent-to-treat (ITT) population of 642 patients (Trial 303) and the other with an ITT population of 630 (Trial 01). The average age was 48 years, and approximately 12% of the participants were older than 65 years. About 90% of the subjects were female.

Subjects met Rome II criteria for chronic constipation, including fewer than three complete spontaneous bowel movements (CSBMs) per week, six or fewer spontaneous bowel movements per week (SBMs), or one or fewer SBMs on the Bristol Stool Form Scale (BSFS). At baseline, subjects reported 0.3 CSBMs per week and about 2 SBMs per week.

Subjects were treated with either 133 mcg or 266 mcg linaclotide or placebo. The linaclotide groups showed significant improvement, compared with placebo on the primary efficacy end point, which was the percentage of patients who had an increase of at least one spontaneous bowel movement over baseline for at least 9 of the 12 treatment weeks. In the first trial, 39.2% of those receiving low-dose linaclotide and 37.0% of those receiving high-dose linaclotide had an increase of one or more CSBMs per week for 9 of 12 weeks, compared with their baseline rate; these rates were significantly greater than the 11% rate observed in the placebo group (P less than .0001). Similar rates were seen in the second trial (31.0% low-dose, 40.1% high-dose, 13% placebo).

Patients also reported improvements in other bowel and abdominal symptoms associated with chronic constipation, such as the weekly rate of CSBMs, weekly rates of SBMs, better stool consistency, less severity of straining, less bloating, less abdominal discomfort, and less constipation severity.

For example, the weekly CSBM rate rose to 2 times per week, compared with 0.5 times per week in the placebo group (P less than .0001). In both trials at both doses tested, patients taking linaclotide reported better quality of life as measured on the 4-point Patient Assessment of Constipation–Quality of Life (PAC-QOL) questionnaire.

Eighty-four percent of enrollees in each trial completed treatment. Analysis of pooled safety results from both trials showed that 7% of those receiving the low dose and 7% of those receiving the high dose of linaclotide discontinued due to adverse events, compared with 4% of those receiving placebo.

One patient receiving low-dose linaclotide died as a result of a fentanyl patch overdose unrelated to the study drug. Diarrhea was the most common adverse event reported by those receiving linaclotide, and 4% of linaclotide-treated patients discontinued due to diarrhea.

During the 4-week randomized withdrawal period, those who were treated with linaclotide during the treatment period were rerandomized to either placebo or the linaclotide dose they had received. Those who had received placebo during the treatment period received high-dose linaclotide during the withdrawal period, explained Dr. Johnston. In total, 538 patients participated in the withdrawal phase.

The investigators found that those who had first received placebo and then received the study drug in the withdrawal phase showed improvements in their constipation symptoms similar to those of the patients who had previously been treated with linaclotide. Those who had received active treatment but were switched to placebo showed regression toward more constipation symptoms, similar to those of the patients who had previously received placebo. No rebound effect was seen after cessation of linaclotide. Sustained improvement was seen in those treated with linaclotide during both the treatment and withdrawal periods.

The trial was supported by Ironwood Pharmaceuticals Inc. Dr. Lembo is a paid consultant to Ironwood Pharmaceuticals. All other authors are employees of either Ironwood Pharmaceuticals or Forest Research Laboratories.

Linaclotide Improved Chronic Constipation in Two Phase III Trials