Table 2. Efficacy Results During the 12-week Treatment Period (ITT Population).
| Placebo | Linaclotide | ||||
|---|---|---|---|---|---|
| 145 μg | 290 μg | ||||
| (N = 171) | (N = 153) | P value | (N = 159) | P value | |
| Primary Endpoint | |||||
| % of patients with ≥ 3 CSBMs/week and increase of ≥ 1 CSBM/week for ≥ 9/12 weeks c | 7.6 | 15.7 | 0.0264*** | 16.4 | 0.0109** |
| Abdominal Bloating | |||||
| Mean abdominal bloating score (11-point NRS) a | 5.5 | 4.7 | 4.6 | ||
| Change from baseline, mean a , b | -1.6 | -2.5 | 0.0002** | -2.5 | 0.0002** |
| % change from baseline, mean a , b | -22.7 | -34.9 | 0.0004** | -34.3 | 0.0006** |
| % change from baseline at week 12, mean b | -30.9 | -44.9 | 0.0030* | -46.5 | 0.0011* |
| % of patients with ≥ 30% weekly mean decrease in abdominal bloating for ≥ 6/12 weeks c | 29.2 | 40.5 | 0.0324** | 43.4 | 0.0083** |
| % of patients with ≥ 50% weekly mean decrease in abdominal bloating for ≥ 6/12 weeks c | 18.1 | 28.8 | 0.0215* | 29.6 | 0.0160* |
| % of patients with ≥ 30% mean decrease in abdominal bloating a , c | 39.2 | 51.0 | 0.0313* | 53.5 | 0.0104* |
| % of patients with ≥ 50% mean decrease in abdominal bloating a , c | 17.5 | 31.4 | 0.0035* | 33.3 | 0.0011* |
| % of patients with ≥ 1-point mean decrease in abdominal bloating a , c | 49.7 | 69.9 | 0.0002* | 67.3 | 0.0012* |
| Change from baseline in % of days with abdominal bloating < 5, mean a , d | 26.7 | 37.7 | 0.0062* | 39.7 | 0.0006* |
| CSBMs | |||||
| Mean CSBMs/week a | 1.2 | 2.5 | 2.5 | ||
| Change from baseline in CSBMs/week, mean a , b | 1.0 | 2.3 | <0.0001** | 2.3 | <0.0001* |
| % of patients with ≥ 3 CSBMs/week for ≥ 9/12 weeks c | 8.2 | 15.7 | 0.0413* | 16.4 | 0.0178* |
| % of patients with increase of ≥ 1 CSBM/week for ≥ 9/12 weeks c | 16.4 | 26.8 | 0.0243* | 29.6 | 0.0045* |
| SBMs | |||||
| Mean SBMs/week a | 3.3 | 5.2 | 5.2 | ||
| Change from baseline in SBMs/week, mean a , b | 1.6 | 3.6 | <0.0001** | 3.6 | <0.0001* |
| Change from baseline in days/week with an SBM, mean a , b | 1.2 | 2.3 | <0.0001** | 2.1 | <0.0001* |
| SBM ≤ 24 hours after first dose, % c | 42.1 | 61.4 | 0.0006** | 59.1 | 0.0022* |
| Time to first SBM after first dose, median number of hours e | 28.1 | 12.5 | 0.0054** | 19.4 | 0.0470* |
| Stool Consistency | |||||
| Mean BSFS score (1–7) a | 3.1 | 4.3 | 4.6 | ||
| Change from baseline, mean a , b | 0.7 | 1.9 | <0.0001** | 2.3 | <0.0001* |
| Straining | |||||
| Mean straining score (1–5) a | 2.8 | 2.2 | 2.1 | ||
| Change from baseline, mean a , b | -0.8 | -1.5 | <0.0001** | -1.5 | <0.0001* |
| % of patients with mean weekly straining score ≤ 2 and no diarrhea AEs for ≥ 9/12 weeks c | 8.8 | 24.8 | 0.0001** | 17.0 | 0.0299* |
| Constipation Severity | |||||
| Mean constipation severity score (1–5) a | 3.1 | 2.7 | 2.6 | ||
| Change from baseline, mean a , b | -0.8 | -1.3 | <0.0001* | -1.4 | <0.0001* |
| Adequate Relief of CIC Symptoms | |||||
| % of patients reporting adequate relief for ≥ 6/12 weeks c | 27.5 | 49.0 | <0.0001* | 50.9 | <0.0001* |
| Rescue Medication Use | |||||
| % of patients with an increase in the percentage of days using rescue medication c | 32.7 | 17.6 | 0.0018* | 13.8 | <0.0001* |
ANCOVA = analysis of covariance; BSFS = Bristol Stool Form Scale; CIC = chronic idiopathic constipation; CSBM = complete SBM; ITT = intent to treat; NRS = numerical rating scale; SBM = spontaneous bowel movement.
*** Primary endpoint (nominal P value)
** Secondary endpoint (nominal P value)
* Additional endpoint
Note: For all primary and secondary efficacy endpoints, the linaclotide groups demonstrated statistically significant improvement compared with the placebo group, controlling for multiplicity.
a Means are over the 12-week treatment period.
b Changes from baseline are the least-squares means from an ANCOVA model; P values were based on a comparison of linaclotide vs. placebo using an ANCOVA model with treatment group and geographic region as factors and corresponding baseline value as a covariate.
c P values were based on a comparison of linaclotide vs. placebo using a Cochran-Mantel-Haenszel test controlling for geographic region.
d Changes from baseline are the arithmetic means; P values were based on a comparison of linaclotide vs. placebo using rank-transformed normal scores in an ANCOVA model with treatment group and geographic region as factors and corresponding baseline value as a covariate.
e P values were based on a comparison of linaclotide vs. placebo time-to-event distributions using log-rank test stratified by geographic region.