Linaclotide, an investigational drug, significantly improved symptoms of chronic constipation in two studies involving 1,276 patients.
"In addition to improving stool frequency, linaclotide significantly improved stool consistency, reduced straining, and reduced abdominal symptoms (bloating and discomfort), which are often reported to be bothersome to patients with chronic constipation," Dr. Anthony J. Lembo of Harvard Medical School, Boston, and his colleagues reported in the Aug. 11 issue of The New England Journal of Medicine.
In patients randomized to active therapy, effects were observed within the first day of treatment and were sustained throughout the 12-week trial.
Linaclotide is a novel synthetic peptide agonist of the guanylate cyclase C receptor on the luminal surface of the intestinal epithelium. The drug’s effects are likely a result of increased luminal fluid with an acceleration of intestinal transit. Additional mechanisms such as reduced visceral hypersensitivity may also contribute to the improvement of abdominal symptoms, the researchers said.
In both trials, patients were randomized to receive once-daily placebo or once-daily treatment with 145 mcg or 290 mcg of linaclotide. Both active treatment doses were associated with significantly greater improvements in bowel and abdominal symptoms, compared with placebo. In the first trial, 21.2% and 19.4% of patients on the 145-mcg and 290-mcg doses, respectively, achieved the study’s primary end point of three or more complete spontaneous bowel movements (CSBMs) per week plus an increase of one or more CSBMs per week over baseline during at least 9 of the 12 study weeks. In the placebo group, 3.3% reached the end point.
During a randomized withdrawal phase following completion of the treatment period, the linaclotide-treated patients were randomized to continue receiving linaclotide at the same dose or to receive placebo. Patients who initially received placebo began receiving 290 mcg of linaclotide. Those who continued on linaclotide or were switched to the active treatment had sustained increases in the rate of CSBMs that were similar to the levels seen during the treatment phase of the study. Those who switched from treatment to placebo experienced a decreased rate of CSBMs similar to the rates in the placebo group during the treatment phase, the investigators said (N. Engl. J. Med. 2011;365:527-36).
The second trial (Trial 01) was identical to the first, but it did not include a randomized withdrawal phase. The primary end point was met by 16% and 21.3% of patients in the 145-mcg and 290-mcg linaclotide groups, compared with 6.0% in the placebo group.
During each week of treatment in both trials, the proportion of patients meeting the primary end point was significantly greater for both doses of linaclotide compared with placebo. Also in both trials, overall response did not significantly differ based on the linaclotide dose.
In both trials and at both doses, linaclotide-treated patients also had significantly greater improvements than did the placebo patients on all secondary end points, including changes in bowel symptoms (the number of weekly CSBMs and spontaneous bowel movements, stool consistency, and straining severity), abdominal symptoms (discomfort and bloating), and constipation severity. However, linaclotide patients had an increased incidence of diarrhea, which prompted 4.2% of treated patients to discontinue. Otherwise, the incidence of adverse events was similar among all study groups, the researchers said.
Quality of life scores improved significantly in the linaclotide patients, compared with the placebo patients. At 12 weeks in Trial 303, 44.9% and 35.5% of those in the 145-mcg and 290-mcg groups, respectively, had an improvement of 1 or more point from baseline on overall Patient Assessment of Constipation Quality of Life (PAC-QOL) scores. In the placebo group, PAC-QOL scores improved in 18.7%. At 12 weeks in Trial 01, improved scores were seen in 42.2% and 46.8% in the 145-mcg and 290-mcg groups, respectively, and in 27.8% on placebo.
"Improvements in the overall and component PAC-QOL scores were significantly greater with both linaclotide doses in each trial, as compared with placebo (with the exception of psychosocial discomfort in Trial 303 for patients given the 290-mcg dose)," the investigators wrote.
Patients in both trials were adults aged 18 and older with chronic constipation who were enrolled into the study at one of 212 participating clinical centers in the United States or Canada from August 20, 2008, through August 12, 2009. Participants were randomized in equal portions to one of the three study groups, and all three groups were well balanced in terms of demographics and baseline bowel and abdominal symptoms.
Linaclotide has the potential to offer multisymptom relief to patients with chronic constipation, but long-term studies are needed to evaluate the safety of long-term treatment, the researchers concluded.