804 participants meeting Rome II criteria for IBS-C. 18+.

Eligibility for randomisation: average score of ≥3 for daily abdominal pain at its worst (11 point rating scale) and an average of <3 Complete Spontaneous Bowel Movements (CSBMs) per week and ≤5 Spontaneous Bowel Movements (SBMs)/week during the baseline period (12 weeks) not necessarily consecutive, in the 12 months before the screening visit.

Mean age 44yrs, Female 90%, White 78%.

Significantly higher proportion of men in placebo arm than the linaclotide arm (12.7 vs 8.2% p=0.037).

Linaclotide 290µg orally once daily, 30 mins before breakfast.

N=401

Placebo

12 weeks and 26 weeks respectively.

1. FDA Responder (Pain ≥50% of weeks).
2. FDA Responder (Stool frequency ≥50% of weeks).
3. FDA Combined responder pain and stool frequency (≥50% of weeks)
4. FDA Pain Responder (≥30% improvement 75% of weeks)
5. FDA Combined responder Pain and stool frequency 75% of weeks
6. Constipation Responder (improvement in stool consistency ≥1 point on BSFS)
7. Bloating Responder (improvement ≥50% wks) Bloating severity (5 point scale).

800 participants

As above (Chey 2012)

Mean age 44 years, 90.5% female.

Linaclotide 290µg once daily. Timing not specified.

N=405

Placebo

1. FDA Responder (Pain ≥50% of weeks).
2. FDA Responder (Stool frequency ≥50% of weeks).
3. FDA Combined responder pain and stool frequency (≥50% of weeks)
4. FDA Pain Responder (≥30% improvement 75% of weeks)
5. FDA Combined responder Pain and stool frequency 75% of weeks
6. Constipation Responder (improvement in stool consistency ≥1 point on BSFS)
7. Bloating Responder (improvement ≥50% wks)
8. Constipation severity (5 point scale).

420 participants

18+ Rome II criteria

<3 SBMs per week and ≥1 of the following for at least 12 wks in the preceding 12 months:

1)

Straining during ≥25% of bowel movements

2)

Lumpy or hard stools during ≥25% of bowel movements

3)

Sensation of incomplete evacuation during ≥25% of bowel movements, plus

Mean score of ≥2 for abdominal (non-menstrual) pain or discomfort on 5 point scale 1=none, 5=very severe) and

Mean of <3 CSBMs and ≤6 SBMs per week.

Discontinuation of ineligible medication (e.g. anticholinergic agents, opiods).

Mean Age 44. Female 92%.

Linaclotide once daily BEFORE first meal. 290µg dose arm reported only.

N=84

Placebo

1. QOL (IBS QOL scale) >14 point change.
2. Mean change from baseline (QOL scale)
3. IBS degree of relief responders (Equivalent to EMA recommended outcome).
4. Constipation Severity

803 participants (Trial 1, Rao (2012) as above.

805 participants (Trial 2, Chey (2012) as above,

Linaclotide 290µg (as above)

Placebo

1. IBS QOL Mean change from baseline* (improvement) by week 12.
2. EMA 12-week abdominal pain/discomfort responders (Pain rated on 11 point NRS. Responder = those with an improvement of ≥30% for at least 6/12 weeks).
3. EMA 26-week abdominal pain/discomfort responders (as above but for 13/26 weeks)
4. EMA 12 week degree of relief responders
5. EMA 26-week degree of relief responders (as above but for at least 13/26 weeks)

62 patients with physician diagnosis of IBS and Rome III criteria for IBSC.

Age 18+

Baseline Characteristics: (not reported by arm)

Mean age (SD) 41.95 (13.56), 85.5% Female.

Average IBS Severity Score at baseline was 296 (95% CI 274,317).

Percentage per score category:

Mild (score<175) - 8.1%

Moderate (175–300) - 46.7%

Severe (>300) - 45.2%

Lubiprostone 48µg, one capsule twice daily.

(n=62 or 60)

Placebo

After treatment period 2

1. Life interference, mean difference
2. IBS-SS Mean difference
3. Pain (0–10 scale) Mean difference
4. Days with hard/lumpy stools or no stools (%)
5. Bloating (0–10 scale) mean difference.

Combined n= 1171

Study A n=590

Study B n=581

Rome II diagnosis of IBS-C. Age 18+.

Compliance with daily diary completion ≥70% during the 4 week baseline period. Min 2 of the following

1. <3 SBMs / week
2. At least 25% SBMs accompanied by at least moderate straining
3. At least 25% SBMs associated with stool consistency rating.

Mean Age 47years, 91.6% female.

Lubiprostone 16µg (8µg twice daily) with breakfast and dinner and with 8oz water

Study A n=390

Study B

N=379

Placebo

1. IBS QOL, mean difference
2. Overall responders (degree of relief over time)
3. Spontaneous Bowel Movements (frequency) Mean difference.

195 participants of 18–80 years old, not pregnant, not lactating.

Rome II diagnostic criteria for IBS

Rome II modular questionnaire criteria for IBS-C

Sigmoidoscopy or colonoscopy within 5 years to rule out other causes/diseases.

In 4 week initiation period

• Avoidance of disallowed medications (not specified)
• Satisfactorily complete electronic diary

Min 2 of the following

1. <3 SBMs / week
2. At least 25% SBMs accompanied by at least moderate straining
3. At least 25% SBMs associated with stool consistency rating

Lubiprostone 16, 32, 48µg per day,

Split into 8µg twice daily (n=51), 16µg twice daily (n=49) or 24µg twice daily (n=45) with breakfast and dinner and 8oz H²0.

Placebo

1. IBS-QOL mean difference
2. Spontaneous bowel movements (weekly frequency) – mean difference
3. Constipation Severity (5 point scale) mean difference.