Table 1.

Summary of randomized, controlled clinical studies of linaclotide in patients with IBS^a.

Study design and patients	Treatment and duration evaluated	Efficacy outcomes	Quality of life	Safety
Primary Analyses
R, DB, PBO-C [Chey et al. 2012] IBS-C (Rome II criteria)	Linaclotide 290 µg qd (n = 402) versus PBO (n = 403) for 26 weeks	Linaclotide versus PBO: FDA endpointb: 6 weeks: 33.7% versus 13.9%, p < 0.0001; 13 weeks: 32.4% versus 13.2%, p < 0.0001 Decrease from baseline ⩾30% in abdominal pain: for ⩾6 weeks: 48.9% versus 34.5%, p < 0.0001; for ⩾9 weeks: 38.9% versus 19.6%, p < 0.0001; for ⩾20 weeks: 36.9% versus 17.4%, p < 0.0001 Increase from baseline ⩾1 CSBM: for ⩾6 weeks: 47.6% versus 22.6%, p < 0.0001; for ⩾9 weeks: 18.0% versus 5.0%, p < 0.0001; for ⩾20 weeks: 15.7% versus 3.5%, p < 0.0001 Decrease from baseline ⩾30% in abdominal pain and ⩾3 CSBMs and increase from baseline ⩾1 CSBM: for ⩾9 weeks: 12.7% versus 3.0%, p < 0.0001; for ⩾20 weeks: 12.0 versus 2.5%, p < 0.0001	Not evaluated	Linaclotide versus PBO: AEs: 65.4% versus 56.6% Diarrhea: 19.7% versus 2.5%
R, DB, PBO-C [Rao et al. 2012] IBS-C (Rome II criteria)	Linaclotide 290 µg qd (n = 405) versus PBO (n = 395) for 12 weeks Withdrawal phase: patients receiving linaclotide for 12 weeks randomized to linaclotide (n = 158) or PBO (n = 154) for 4 weeks; patients receiving PBO for 12 weeks assigned to linaclotide (n = 335) for 4 weeks	Linaclotide versus PBO: 12-week tx phase: FDA endpointb: 33.6% versus 21.0%, p < 0.0001 Decrease from baseline ⩾30% in abdominal pain for ⩾6 weeks: 50.1% versus 37.5%, p = 0.0003 Increase from baseline ⩾1 CSBM for ⩾6 weeks: 48.6% versus 29.6%, p < 0.0001 Decrease from baseline ⩾30% in abdominal pain for ⩾9 weeks: 34.3% versus 27.1%, p = 0.03 ⩾3 CSBMs and increase from baseline ⩾1 CSBM for ⩾9 weeks: 19.5% versus 6.3%, p < 0.0001 Decrease from baseline ⩾30% in abdominal pain and ⩾3 CSBMs and increase from baseline ⩾1 CSBM for ⩾9 weeks: 12.1% versus 5.1%, p = 0.0004 4-week withdrawal phase: Re-randomized from linaclotide to PBO: increase in worst abdominal pain and decrease in CSBMs comparable with PBO group in 12-week tx phase Continuation of linaclotide: continued improvement in worst abdominal pain and CSBMs Switch from PBO to linaclotide: improvement in worst abdominal pain and CSBMs comparable with linaclotide group in 12-week tx phase	Not evaluated	Linaclotide versus PBO: 12-week tx phase: AEs: 56.2% versus 53.0% Diarrhea: 19.5% versus 3.5% Abdominal pain: 5.4% versus 2.5% Headache: 4.9% versus 3.5% Flatulence: 4.9% versus 1.5% Abdominal distension: 2.2% versus 0.8% 4-week withdrawal phase: Linaclotide-linaclotide: 22.2% Linaclotide-PBO: 22.1% PBO-linaclotide: 30.6%
Post hoc analyses
R, DB, PBO-C [Castro et al. 2013] Post hoc longitudinal responder analysis of patients with IBS-C	Linaclotide 290 µg qd versus PBO for 26 weeks (pooled,N = 805)	Decrease ⩾30% from baseline in abdominal pain in patients receiving linaclotide Week 3: >50% of patients Week 7: >60% of patients Week 26: ~70% of patients (p < 0.005 versus PBO for each of 26 weeks)	Not evaluated	Not evaluated
R, DB, PBO-C [Quigley et al. 2013] Post hoc analysis [Cheyet al. 2012; Rao et al. 2012] of patients with IBS-C (Rome II criteria) and mean daily abdominal pain severity score ⩾3.0	Linaclotide 290 µg qd versus PBO for 12 weeks	Linaclotide versus PBO: EMA endpoint for abdominal pain or discomfortc: Trial 31: 54.8% versus 41.8%, p < 0.001 Trial 302: 54.1% versus 38.5%, p < 0.0001 EMA endpoint for degree of relief of IBS symptomsd: Trial 31: 37.0% versus 18.5%, p < 0.0001 Trial 302: 39.4% versus 16.6%, p < 0.0001	Linaclotide versus PBO (LS mean change): Improvement in IBS-QOL from baseline to Week 12: Trial 31: 18.4 versus 15.2,p = 0.004; Trial 302: 16.6 versus 11.1,p < 0.0001 Improvement in EQ-5D from baseline to Week 12: Trial 31: 0.08 versus 0.05,p = 0.001; Trial 302: 0.08 versus 0.04,p = 0.0005 Improvement in EQ-5D VAS from baseline to Week 12: Trial 31: 5.6 versus 3.7,p = 0.06; Trial 302: 7.1 versus 4.4,p = 0.006	Not further evaluated
R, DB, PBO-C [Macdougallet al. 2013] Post hoc analysis [Cheyet al. 2012; Rao et al. 2012] of patients with IBS-C (Rome II criteria)	Linaclotide 290 µg qd versus PBO for 12 weeks (pooled, N = 1602)	Linaclotide versus PBO: FDA endpointb: 33.7% versus 17.4%, p < 0.0001	Not evaluated	Not evaluated
R, DB, PBO-C [Rao et al. 2014] Post hoc analysis [Cheyet al. 2012; Rao et al. 2012] of patients with IBS-C (Rome II criteria) and baseline abdominal symptom severity score ⩾7.0) Patients with severe abdominal symptoms: fullness (44%), bloating (44%), discomfort (32%), pain (23%), cramping (22%)	Linaclotide 290 µg qd (n = 805) versus PBO (n = 797) for 12 weeks (pooled, N = 1602)	Significant change from baseline in severe abdominal symptoms (pain, discomfort, bloating, fullness, cramping) with linaclotide versus PBO at Week 12 (p < 0.0001 for all comparisons) Adequate relief of IBS symptoms significantly greater with linaclotide versus PBO at Week 12 (59–61% versus 28–32%, p < 0.0001)	Response by IBS-QOL in 62–68% of patients receiving linaclotide versus 45–47% of patients receiving PBO (p < 0.01)	Linaclotide versus PBO: Diarrhea: 18.3–19.8% versus 1.6–2.1% Flatulence: 4.2–5.7% versus 1.8–2.5% Abdominal pain: 2.1–4% versus 2.2–2.5%

^aStudies presented are limited to the previous 4 years, due to the large number of clinical studies of linaclotide.

^bDefined as meeting both an improvement from baseline ⩾30% in mean of daily worst abdominal pain scores and an increase from baseline ⩾1 CSBM for ⩾6 weeks of first 12 weeks of treatment.

^cAbdominal pain responder defined as patient with improvement from baseline ⩾30% in mean weekly worst abdominal pain score or mean weekly abdominal discomfort score for ⩾6 weeks of first 12 weeks of treatment, with neither score worsening from baseline. Scoring of abdominal pain or discomfort ranged from 0 (none) to 10 (very severe).

^dDegree-of-relief responder defined as patient with ‘considerable’ or ‘complete’ relief of IBS symptoms (i.e. score ⩽2) for ⩾6 of first 12 weeks of treatment. Symptoms were rated weekly on a scale of 1 to 7, with rating of 1 for ‘completely relieved’, 4 for ‘unchanged’, and 7 for ‘as bad as I can imagine’.

AE, adverse event; CSBM, complete spontaneous bowel movement; DB, double-blind; EMA, European Medicines Agency; EQ-5D, European Quality of Life - 5 Dimensions; EQ-5D VAS, European Quality of Life - 5 Dimensions Visual Analogue Scale; IBS-C, constipation-predominant irritable bowel syndrome; IBS-QOL, Irritable Bowel Syndrome - Quality Of Life questionnaire; LS, least squares; PBO, placebo; PBO-C, placebo-controlled; qd, once daily; R, randomized; tx, treatment.