The efficacy of linaclotide in patients with chronic constipation was initially evaluated in a randomized, double-blind, placebo-controlled pilot study. Forty-two patients with chronic constipation were randomized to linaclotide (100, 300, or 1000 μg) or placebo once daily for 14 days to evaluate the safety, tolerability, and efficacy of the drug. A significant increase in the frequency of spontaneous bowel movements occurred with the 100 μg dose compared with placebo (change 6.18 versus 2.76 for placebo, P
= 0.047). Frequency of complete and spontaneous bowel movements (CSBMs) also increased, with mean changes of 2.16, 2.90, and 3.19 for the 100, 300 and 1000 μg doses, respectively, versus 1.30 for placebo. The authors considered CSBM to be a more clinically meaningful endpoint than spontaneous bowel movement because epidemiologic surveys have found that many constipated persons do not qualify for constipation by Rome II criteria based on stool frequency alone. This is because most constipated persons complain of defecation difficulties and/or a sense of incomplete evacuation.13
Stool consistency also improved in a dose-related manner in all three drug groups, with a statistically significant increase with the 1000 μg dose versus placebo (change 2.58 versus 0.43 for placebo, P
= 0.014). Straining improved in all groups, with the greatest improvement with the higher doses (change 1.33 and 1.51 for 300 μg and 1000 μg, respectively, versus 0.36 for placebo). Dose-related improvements were also seen in abdominal discomfort (mean scores decreased from baseline by −0.58, −0.76, and −0.85 for linaclotide 100, 300, and 1000 μg, respectively, versus −0.16 for placebo), overall relief, and severity of constipation. The effect on bowel habits occurred within the first few days of treatment and overall relief of constipation occurred within the first week. The improvement scores regressed towards baseline after the drug was stopped. Because there was no worsening compared with baseline, the authors concluded that there was no evidence of a rebound effect.14
A subsequent dose-ranging study of chronic constipation was done with larger numbers of patients and a longer duration of treatment. In this multicenter, double-blind trial, 310 patients with chronic constipation, as defined by Rome II criteria, were randomized into groups given 75, 150, 300, or 600 μg oral linaclotide or placebo once daily for 4 weeks. Rescue medications were allowed, including oral bisacodyl (up to 15 mg daily), Fleets enema, or bisacodyl suppositories, but no more than two rescue medications were allowed in the pretreatment period. Mean increases in frequency of spontaneous bowel movement exhibited a linear dose response with increases of 2.6, 3.3, 3.6, and 4.3 for doses of 75, 150, 300, and 600 μg, respectively, compared with 1.5 for placebo (P
< 0.05). Patients receiving drug were more likely to have a spontaneous bowel movement within the first 24 hours (50.8%, 55.4%, 54.8%, and 75.8%, respectively, for the four doses) compared with placebo (36.8%, P
< 0.05). The median time to first spontaneous bowel movement was 24.0, 21.9, 23.1, and 13.0 hours for the four doses versus 32.6 hours for placebo (P
= 0.0005 for overall log-rank test). Similar changes were seen for mean weekly CSBM frequency. Improvement in overall stool consistency was also dose-related, as was overall straining. Bowel habits returned to baseline patterns during the post-treatment period, suggesting no rebound worsening of constipation. The percentage of patients who reported a decrease in the abdominal discomfort score (defined as ≥0.5 for 3 of 4 weeks) ranged from 27% to 32% for the four linaclotide doses versus 12% for placebo (P
< 0.05 for each dose). Similarly, the percentage of patients who reported a decrease in the bloating score (defined as ≥0.5 for 3 of 4 weeks) ranged from 29% to 39% for linaclotide versus 12% for placebo (P
< 0.05). All three global measures, including constipation severity, adequate relief of constipation, and relief of constipation, improved in dose-dependent manner. Of note, there was no significant change in rescue medication use between the placebo and linaclotide groups.15
In 2011, the results of two Phase III trials in chronic constipation were reported. Two randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled trials were performed at 204 clinical centers in the US and at eight clinical centers in Canada. The trials were identical except that one trial included a 4-week period of randomized withdrawal at the conclusion of the 12-week treatment period. In a ratio of 1:1:1, patients were randomly given 145 μg or 290 μg of linaclotide, or placebo. After completing the treatment period, patients in one trial who had received linaclotide during the preceding treatment period were randomly assigned to either the same linaclotide dose or placebo, whereas patients who had received placebo during the treatment period were given 290 μg of linaclotide for a 4-week period.
Eligible patients who met the criteria for chronic constipation reported fewer than three spontaneous bowel movements per week (without laxatives, enemas, or suppositories in the preceding 24 hours) and straining, lumpy, or hard stools or a sensation of incomplete evacuation for more than 25% of bowel movements for at least 12 weeks within the preceding 12 months. In addition, during the 14-day baseline period, patients had to report an average of fewer than six spontaneous bowel movements and fewer than three CSBMs per week. The primary endpoint of both trials was defined as both three or more CSBMs per week and an increase of at least one CSBM per week from baseline for at least 75% of the weeks of the treatment period. Secondary endpoints included stool frequency, stool consistency, severity of straining, abdominal discomfort, bloating, and constipation severity. Additional endpoints such as constipation relief, satisfaction with treatment, the likelihood of treatment continuation, and health-related quality of life were determined.
A total of 1272 patients (642 in trial 303 and 630 patients in trial 01) were included in the intention-to-treat analysis; rates of compliance during the treatment period were over 86%. In the two trials, 21.2% and 16.0% of the patients who received the 145 μg dose and 19.4% and 21.3% of the patients who received the 290 μg dose, respectively, met the primary endpoint versus 3.3% and 6.0% with placebo (P
< 0.01 for each dose). In both trials, differences in overall response rates between the two linaclotide doses were not statistically significant. For all secondary endpoints, linaclotide-treated patients had significant improvements versus placebo. Weekly CSBM rates increased significantly with linaclotide in the first week and were maintained throughout the 12-week period. In both trials, scores for constipation relief, treatment satisfaction, and treatment continuation were significantly greater in both treatment groups than in the placebo group. At week 12, 44.9% and 42.2% of respective patients who received 145 μg and 35.5% and 46.8% of those who received 290 μg of linaclotide had improved by one point or more from baseline in overall Patient Assessment of Constipation Quality of Life score, compared with 18.7% and 27.8% who received placebo (P
< 0.01). In trial 303, which included an additional 4 weeks, patients who continued to take linaclotide and those who were switched from placebo to linaclotide had sustained increases in the frequency of CSBMs similar to levels reported during the treatment period, whereas patients who switched from linaclotide to placebo had a decreased frequency of CSBMs.16