Table 2. Efficacy results during the 12-week treatment period (ITT population)Continued.
| Placebo (N=401) |
Linaclotide |
||||
| 72 μg (N=411) | P-value OR (95% CI) | 145 μg (N=411) | P-value OR (95% CI) | ||
| Primary endpoint a: 12-week CSBM overall responder | |||||
| b% 12-week CSBM overall responders: % of patients with ≥3 CSBMs/week and an increase of ≥1 CSBM/week (CSBM weekly responders) for ≥9 of 12 weeksc, d | 4.7 | 13.4 | <0.0001a 3.0 (1.8, 5.2) | 12.4 | <0.0001 2.8 (1.6, 4.9) |
| Secondary and additional endpoints | |||||
| CSBM | |||||
| Mean CSBMs/weekd | 1.0 | 1.8 | 2.0 | ||
| eChange from baseline in CSBMs/week, meand, f | 0.9 | 1.7 | <0.0001a | 1.9 | <0.0001 |
| e% CSBM weekly responders for ≥3 of 4 weeks in month 1 of treatmentc | 6.2 | 14.8 | <0.0001a 2.6 (1.6, 4.2) | 15.8 | <0.0001 2.8 (1.7, 4.6) |
| e% CSBM weekly responders for ≥3 of 4 weeks in month 2 of treatmentc | 9.5 | 18.7 | 0.0002a 2.2 (1.4, 3.3) | 19.0 | 0.0002 2.2 (1.5, 3.4) |
| e% CSBM weekly responders for ≥3 of 4 weeks in month 3 of treatmentc | 14.2 | 20.2 | 0.0342a 1.5 (1.0, 2.2) | 20.0 | 0.0385 1.5 (1.0, 2.2) |
| e% CSBM weekly responders for ≥9 of 12 weeks (>1 SBM/week at BL subpopulation)c, d | 7.1 | 17.2 | 0.0008a 2.7 (1.5, 4.9) | 17.4 | 0.0009 2.7 (1.5, 5.0) |
| Sustained responder | |||||
| % CSBM weekly responders for ≥9 of 12 weeks, including 3 of 4 final treatment weeksc, d | 4.7 | 12.4 | 0.0001 2.8 (1.6, 4.8) | 11.2 | 0.0010 2.5 (1.4, 4.4) |
| SBM | |||||
| Mean SBMs/weekd | 2.7 | 3.9 | 4.1 | ||
| eChange from baseline in SBMs/week, meand, f | 1.3 | 2.4 | <0.0001a | 2.6 | <0.0001 |
| Stool consistency (BSFS) | |||||
| Mean BSFS/weekd | 3.0 | 3.6 | 3.7 | ||
| eChange from baseline, meand, f | 1.1 | 1.7 | <0.0001a | 1.8 | <0.0001 |
| Straining | |||||
| Mean straining score (1 to 5-point ordinal scale)d | 2.7 | 2.5 | 2.3 | ||
| eChange from baseline, meand, f | −0.8 | −1.1 | <0.0001a | −1.2 | <0.0001 |
| Abdominal bloating | |||||
| Mean abdominal bloating score (11-point NRS)d | 4.2 | 3.8 | 3.7 | ||
| eChange from baseline, meand, f | −1.1 | −1.4 | 0.0063a | −1.5 | <0.0001 |
| Abdominal discomfort | |||||
| Mean abdominal discomfort score (11-point NRS)d | 3.6 | 3.3 | 3.3 | ||
| eChange from baseline, meand, f | −1.1 | −1.3 | 0.1028 | −1.4 | 0.0056 |
| Abdominal pain | |||||
| Mean abdominal pain score (11-point NRS)d | 3.2 | 2.9 | 2.9 | ||
| Change from baseline, meand, f | −1.0 | −1.2 | 0.0183 | −1.3 | 0.0029 |
| Constipation severity | |||||
| Mean constipation severity score (11-point NRS)d | 3.0 | 2.7 | 2.6 | ||
| Change from baseline, meand, f | −0.6 | −0.9 | <0.0001 | −1.0 | <0.0001 |
| Degree of relief of constipation | |||||
| % of patients at least ‘somewhat relieved’ for all 12 weeks or at least ‘considerably relieved’ for 6 of 12 weeks of treatmentc | 24.2 | 36.0 | 0.0004 | 36.0 | 0.0003 |
| Treatment satisfaction | |||||
| Mean treatment satisfaction at Week 12 (1 to 5-point ordinal scale)d | 2.9 | 3.4 | <0.0001 | 3.5 | <0.0001 |
| PAC-QOL—overall score | |||||
| Mean score at Week 12 (5-point scale)g | 1.4 | 1.2 | 1.1 | ||
| Change from baseline, meanf | −0.7 | −1.0 | <0.0001 | −1.0 | <0.0001 |
| Rescue medication use (bisacodyl) | |||||
| Mean percent of days during treatment | 8.7 | 9.5 | 9.4 | ||
| Change from baseline, meanf | −0.5 | <0.1 | 0.6752 | 0.3 | 0.5570 |
ANCOVA, analysis of covariance; BSFS, Bristol Stool Form Scale; CI, confidence interval; CSBM, complete SBM; ITT, intent to treat; MCP, multiple comparisons procedure; NRS, numerical rating scale; OR, odds ratio; PAC-QOL, Patient Assessment of Constipation—Quality of Life; SBM, spontaneous bowel movement.
Statistically significant under the MCP.
Primary endpoint: linaclotide 72 μg dose compared with placebo for 12-week CSBM overall responder evaluated under a multiple comparisons procedure (MCP); linaclotide 145 μg was evaluated for comparison purposes only and was not subjected to the MCP.
Odds ratios, 95% confidence intervals, and P values were based on a comparison of linaclotide vs. placebo using a Cochran-Mantel-Haenszel test controlling for SBM stratum (except for >1 SBM/week subpopulation analysis) and geographic region.
Means are over the 12-week treatment period.
Secondary endpoint: linaclotide 72 μg dose compared with placebo for the parameter specified, under the MCP; linaclotide 145 μg was evaluated for comparison purposes only and was not subjected to the MCP.
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, baseline SBM stratum, and geographic region as factors and corresponding baseline value as a covariate.
Composite of four 0- to 4-point subscales, using a last observation carried forward approach to missing data. Lower score indicates better outcome.