Table 2.
Phase III clinical trials of linaclotide in constipation-predominant irritable bowel syndrome.
| Study/phase/design | Number of patients/sex/duration/doses studied | Primary endpoints | Efficacy results | Selected secondary endpoints | Efficacy results |
|---|---|---|---|---|---|
| Rao et al. [2012] | N = 800 | FDA endpoint* | 33.6% versus 21% met the FDA endpoint (p < 0.0001) | 12-week change from baseline: | |
| Phase III, randomized, double-blind, placebo-controlled trial | Female patients = 90.5% | Three responder definitions** | NNT = 7.9 | Worst abdominal pain | 50.1% versus 37.5% had a ≥30% reduction in abdominal pain (p = 0.0003) |
| 12-week treatment period followed by a 4-week randomized withdrawal period | (>9 of the 12 weeks of therapy) | Greater proportion of linaclotide treated versus placebo treated met the three responder definitions | Abdominal discomfort | 48.1% versus 37% had a ≥30% reduction in abdominal discomfort (p = 0.0001) | |
| Placebo, 290 µg linaclotide | NNT range 7.6–14.3 | Abdominal bloating | 43.5% versus 29.9% had a ≥30% reduction in abdominal bloating (p < 0.0001) | ||
| EMA 12-week abdominal pain/discomfort endpoint | Stool frequency (CSBM rate) | 48.6% versus 29.6% had a ≥1 CSBM rate increase for ≥6/12 weeks (p < 0.0001) | |||
| NNT = 7.69 | Stool frequency (SBM rates) | 57.5% versus 29.4% had a ≥2 SBM rate increase for ≥6/12 weeks (p < 0.0001) | |||
| EMA 12-week IBS degree-of-relief endpoint | BSFS stool consistency | 79.4% versus 60.7% had a BSFS ≥3 (p < 0.0001) | |||
| NNT = 5.41 | Severity of straining | 85.3% versus 71.7% had strain score ≤3 (p < 0.0001) | |||
| Chey et al. [2012] | N = 804 | FDA endpoint* | 33.7% versus 13.9% met the FDA endpoint (p < 0.0001) | 12 week change from baseline: | |
| Phase III, randomized, double-blind, placebo-controlled trial | Female patients = 90% | Three responder definitions** | NNT = 5.1 | Worst abdominal pain | 48.9% versus 34.5% had a ≥30% reduction in abdominal pain (p < 0.0001) (NNT = 7) |
| 26-week treatment period | (>9 of the first 12 weeks of therapy) | Greater proportion of linaclotide treated versus placebo treated met the three responder definitions | Abdominal discomfort | 47.6% versus 30.8% had a ≥30% reduction in abdominal discomfort (NNT = 5.9) | |
| Placebo, 290 µg linaclotide | Efficacy parameters over 26-week time period | NNT range 5.2–10.3 | Abdominal bloating | 42.9% versus 23.8% had a ≥30% reduction in abdominal bloating (NNT = 5.2) | |
| EMA 12-week abdominal pain/discomfort endpoint | Stool frequency (CSBM rate) | 47.6% versus 22.6% had a ≥1 CSBM rate increase for ≥6/12 weeks (NNT = 4) | |||
| NNT = 6.41 | Stool frequency (SBM rates) | 55.4% versus 27.8% had a ≥2 SBM rate increase for ≥6/12 weeks (NNT = 3.6) | |||
| EMA 26-week abdominal pain/discomfort endpoint | BSFS stool consistency | 80.3% versus 61.1% had a BSFS ≥3 (NNT = 5.21) | |||
| NNT = 5.68 | Severity of straining | 82.4% versus 70.6% had strain score ≤3 (NNT=8.48) | |||
| EMA 12-week IBS degree-of-relief endpoint | 26-week change from baseline: | 49.1% versus 31.3% had a ≥30% reduction in abdominal pain (p < 0.0001) (NNT = 5.6) | |||
| NNT = 4.39 | Worst abdominal pain | 48.1% versus 28.8% had a ≥30% reduction in abdominal discomfort (NNT = 5.2) | |||
| EMA 26-week IBS degree-of-relief endpoint | Abdominal discomfort | 42.4% versus 25.1% had a ≥30% reduction in abdominal bloating (NNT = 5.8) | |||
| NNT=4.93 | Abdominal bloating | 43.6% versus 18.6% had a ≥1 CSBM rate increase for ≥6/12 weeks (NNT = 4) | |||
| Stool frequency (CSBM rate) | 49.6% versus 21.6% had a ≥2 SBM rate increase for ≥6/12 weeks (NNT = 3.6) | ||||
| Stool frequency (SBM rates) | 81% versus 62.1% had a BSFS ≥3 (NNT = 5.29) | ||||
| BSFS stool consistency | 83.5% versus 71.6% had strain score ≤3 (NNT = 8.40) | ||||
| Severity of straining |
BSFS, Bristol Stool Form Scale; CSBM, complete spontaneous bowel movement; FDA, US Food and Drug Administration; EMA, European Medicines Agency; IBS, irritable bowel syndrome; NNT, number needed to treat; SBM, spontaneous bowel movement.
*
≥30% improvement in the average daily worst abdominal pain score and increase by ≥ 1 CSBMs from baseline, occurring in the same week for at least 6 of the 12 weeks of therapy **(i) ≥ 30% improvement in abdominal pain scores, (ii) ≥ 3 CSBMs and an increase ≥ 1 CSBM from baseline, and (iii) a combined end point defined as a responder patient who met criteria for both (i) and (ii) in the same week