Table 1 SBM outcomes for lubiprostone, linaclotide, and elobixibat

Eguchi, 2020

Lubiprostone

• Population: ≥65 years (80%)

• Population type: CC

• Sample size: 1,338

• Design: Retrospective single-arm study

• Region: Japan

• SBM frequency (no./wk)

Week 2

SBM frequency: mean (SD)

• Before: 2.7 (2.7)

• After: 5.3 (6.9); p < 0.01

Note: There were 34 (2.5%) patients who did not respond to the 2 weeks treatment with Lubi.

Fukudo, 2015

Lubiprostone

• Population: Adults

• Population type: CIC

• Sample size: 124

• Design: RCT, phase III

• Region: Japan

• Change from baseline in SBM frequency (no./wk)

• SBM ≤ 24 h

• SBM ≤ 48 h

• Responder rate (> 4 SBMs/wk)

SBM frequency, mean (SD) at baseline,

• Lubi 48 mcg: 1.65 (0.78)

• PBO: 1.68 (0.77), p = 0.873

Change from baseline in SBM frequency, mean (SE)

• Week 1: Lubi 48 mcg: 3.7 (2.8); PBO: 1.3 (1.8), (p < 0.001)

• Week 2: Lubi 48 mcg: 2.74; PBO: 1.33, (p < 0.001)

• Week 3: Lubi 48 mcg: 2.75; PBO: 1.51, (p < 0.005)

• Week 4: Lubi 48 mcg: 2.56; PBO: 1.62, (p = 0.042)

SBM ≤ 24 h (%):

• Lubi 48 mg: 58.1%; PBO: 30.6%, (p = 0.004)

SBM ≤ 48 h (%):

• Lubi 48 mcg: 80.6%; PBO: 64.5%, (p = 0.069)

Responder rate (%)

• Week 1: Lubi 48 mcg: 75.4%; PBO: 29.0% (p = 0.001)

• Week 2: Lubi 48 mcg: 53.4%; PBO: 40.0% (p = 0.196)

• Week 3: Lubi 48 mcg: 54.4%; PBO: 37.7% (p = 0.096)

• Week 4: Lubi 48 mcg: 54.2%; PBO: 36.7% (p = 0.066)

Fukudo, 2011

Lubiprostone

• Population: Adults

• Population type: CIC plus IBS-C

• Sample size: 170

• Design: RCT phase II (dose-finding study)

• Region: Japan

• Change from baseline in SBM frequency (no./wk)

• SBM ≤ 24 h

• SBM ≤ 48 h

Week 1

Change from baseline in SBM frequency, mean (SE)

• Lubi 48 mcg: 6.8 (1.1), (p < 0.0001, vs. PBO)

• PBO: 1.5 (0.4)

SBM ≤ 24 h (n%)

• Lubi 48 mcg: 75%, (p < 0.0001, vs. PBO)

• PBO: 26.2%

SBM ≤ 48 h (n%):

• Lubi 48 mcg: 97.7%, (p < 0.0001, vs. PBO)

• PBO: 57.1%

Johanson, 2008

Lubiprostone

• Population: Adults

• Population type: CC

• Sample size: 242

• Design: RCT; phase III

• Region: USA

• SBM frequency (no./wk)

• SBM ≤ 24 h

• SBM ≤ 48 h

• Responder rate (≥ 3 SBMs/wk)

SBM frequency, mean (SD)

• Baseline: Lubi: 1.37 (0.87); PBO: 1.47 (1.33)

• Week 1: Lubi: 5.69; PBO: 3.46 (p = 0.0001)

• Week 2: Lubi: 5.06; PBO: 3.18 (p ≤ 0.002)

• Week 3: Lubi: 5.25; PBO: 2.84 (p ≤ 0.002)

• Week 4: Lubi: 5.30; PBO: 2.91 (p ≤ 0.002)

SBM ≤ 24 h (%)

• Lubi: 56.7%; PBO: 36.9%; (p = ≤ 0.0024, vs. PBO)

SBM ≤ 48 h (%)

• Lubi: 80%; PBO: 60.7%; (p = 0.0013, vs. PBO)

Responder rate (%)

• Week 1: Lubi: 64.7%; PBO: 43.4% (p < 0.004)

• Week 2: Lubi: 57.8%; PBO: 36.1% (p < 0.004)

• Week 3: Lubi: 56.0%; PBO: 28.7% (p < 0.004)

• Week 4: Lubi: 57.8%; PBO: 27.9% (p < 0.004)

Johanson, 2007

Lubiprostone

• Population: Adults

• Population type: CC

• Sample size: 127

• Design: RCT; phase II (dose-ranging study)

• Region: USA

• SBM frequency (no./wk)

• SBM ≤ 24 h

SBM frequency

Week 1

• Lubi 48 mcg: (p = 0.002, vs. PBO)

Week 2

• Lubi 48 mcg: (p ≤ 0.020, vs. PBO)

SBM ≤ 24 h (%)

• Lubi 48 mcg (24 mcg b.d.): 59.4%; (p = 0.009)

Barish, 2010

Lubiprostone

•Population: Adults

•Population type: CC

•Sample size: 237

•Design: RCT; phase 3; global

• Frequency of SBMs (no./wk)

• SBM ≤ 24 h (%)

• Responder rate (%):

• Full responders: (SBM frequency ≥ 4 per week)

Frequency of SBMs

•Baseline: Lubi 48 mcg:1.28, PBO: 1.5 (p = 0.0126)

•Week 1: Lubi 48 mcg: 5.89, PBO: 3.99 (p < 0.0001)

•Week 2: Lubi 48 mcg: 4.96, PBO: 3.55 (p < 0.0487)

•Week 3: Lubi 48 mcg: 5.56, PBO: 3.36 (p < 0.0004)

•Week 4: Lubi 48 mcg: 5.37; PBO: 3.46 (p < 0.0068)

SBM ≤ 24 h (%):

•Week 1: Lubi 48 mcg: 61.3%

•PBO: 31.4% (p < 0.0001)

Responder rate, full responder (n%)

•Week 1: Lubi 48 mcg: 72%, PBO: 49%; (p < 0.0001)

•Week 2: Lubi 48 mcg: 58%, PBO: 43%; (p = 0.0171)

•Week 3: Lubi 48 mcg: 61%, PBO: 36%; (p = 0.0002)

•Week 4: Lubi 48 mcg: 60%, PBO: 39%; (p = 0.0002)

Fukudo, 2019

Linaclotide

• Population: Adults

• Population type: CC

• Sample size: 181

• Design: RCT, phase III

• Region: Japan

• SBM frequency (no./wk)

• Change from baseline in SBM frequency (no./wk)

• SBM ≤ 24 h

• Responder rate (> 3 SBMs/wk)

Week 1

SBM frequency: mean (95% CI)

• Lina 500 mcg: 5.72 (5.10, 6.35)

• PBO: 3.19 (2.55, 3.82); p < 0.001

Change from baseline in SBM frequency, mean (95% CI)

• Lina 500 mcg: 4.02 (3.39, 4.64)

• PBO: 1.48 (0.85, 2.12); p < 0.001

SBM ≤ 24 h (%, 95% CI)

• Lina 500 mcg:72.8 (62.6, 81.6); p < 0.001

• PBO: 48.3 (37.6, 59.2)

Responder rate: Mean (95% CI).

1st week:

• Lina 500 mcg: 83.5 (74.3, 90.5)

• PBO: 56.8 (45.8, 67.3); p < 0.001

2nd of 4 weeks:

• Lina 500 mcg: 83.5 (74.3, 90.5)

• PBO: 64.8 (53.9, 74.7); p = 0.006

3rd of 4 weeks:

• Lina 500 mcg: 71.4 (61.0, 80.4)

• PBO: 42.0 (31.6, 53.0); p < 0.001

Fukudo, 2018

Linaclotide

• Population: Adults

• Population type: CC

• Design: RCT; phase II (dose-finding study)

• Sample size: 382

• Region: Japan

• SBM frequency (no./wk)

• Change from baseline in SBM frequency (no./wk)

• Responder rate (%) (> 3 SBMs/wk)

SBM frequency: mean.

Week 1

• Lina 500 mcg: 5.58; p < 0.001

• PBO: 3.64

Week 2

• Lina 500 mcg: 5.70; p < 0.001

• PBO: 3.27

Change from baseline in SBM frequency, Mean.

Week 1

• Lina 500 mcg: 3.85; p < 0.001

• PBO: 1.91

Week 2

• Lina 500 mcg: 3.96; p < 0.001

• PBO: 1.53

Responder Rate (%):

Week 1

• Lina 500 mcg: 77.6%; p = 0.037

• PBO: 61.3%

Week 2

• Lina 500 mcg: 82.7%; p = 0.002

• PBO: 60%

Schoenfeld, 2018

Linaclotide

• Population: Adults

• Population type: CIC

• Design: RCT; phase III, (NCT02291679)

• Sample size: 1223

• Region: USA

• SBM frequency (no./wk)

• Change from baseline in SBM frequency (no./wk)

Week 12

SBM frequency: mean.

• Lina 145 mcg: 4.1

• PBO: 2.7

Change from baseline in SBM frequency, mean.

• Lina 145 mcg: 2.6; p < 0.0001

• PBO: 1.3

Lacy, 2015

Linaclotide

• Population: Adults

• Population type: CIC

• Design: RCT; phase IIIb, (NCT01642914)

• Sample size: 483

• Region: USA/Canada

• SBM frequency (no./wk)

• Change from baseline in SBMs/wk

• Change from baseline in days/wk with an SBM

• SBM ≤ 24 h

Week 12

SBM frequency: mean

• Lina 145 mcg: 5.2*

• PBO: 3.3*

*Note: Over the 12-week treatment period.

Change from baseline in SBM frequency, LS mean

• Lina 145 mcg: 3.6; (p < 0.0001, vs. PBO)

• PBO: 1.6

Change from baseline in days/week with an SBM: mean

• Lina 145 mcg: 2.3; (p < 0.0001, vs. PBO)

• PBO: 1.2

SBM ≤ 24 h (%):

• Lina 145 mcg: 61.4%; (p < 0.0006, vs. PBO)

Lembo, 2011a

Lembo, 2011b

Linaclotide

• Population: Adults

• Population type: CC

• Design: RCT (Trial 303); phase III; (NCT00730015)

• Sample Size: 642

• Region: USA/Canada

• SBM frequency (no./wk)

• Change from baseline in SBM frequency (no./wk)

• SBM ≤ 24 h

• Increase of ≥ 2 SBMs for 9 of 12 wk

Week 12

SBM frequency: mean

• Lina 145 mcg: 5.2

• PBO: 3.2

Change from baseline in SBM frequency, mean

• Lina 145 mcg: 3.0; p < 0.001

• PBO: 1.1

SBM ≤ 24 h (%):

• Lina 145 mcg: 70% p < 0.001

• PBO: 39.7%

Increase of ≥ 2 SBMs for 9 of 12 wk (%)

• Lina 145 mcg: 41% p < 0.001

• PBO: 12.9%

Linaclotide

• Population: Adults

• Population type: CC

• Design: RCT (Trial 01); phase III; (NCT00765882)

• Sample size: 630

• Region: USA/Canada

• SBM frequency (no./wk)

• Change from baseline in SBM frequency (no./wk)

• SBM ≤ 24 h

• Increase of ≥ 2 SBMs for 9 of 12 wk

Week 12

SBM frequency: mean

• Lina 145 mcg: 5.3

• PBO: 3.0

Change from baseline in SBM frequency, mean

• Lina 145 mcg: 3.4; p < 0.001

• PBO: 1.1

SBM ≤ 24 h (%):

• Lina 145 mcg: 64.3%; p < 0.001

• PBO: 39.1

Increase of ≥ 2 SBMs for 9 of 12 wk (%):

• Lina 145 mcg: 39% P < 0.001

• PBO: 16.3

Tomie, 2020

Elobixibat

• Population: Elderly

• Population type: CC

• Design: RCS

• Sample size: 104

• Region: Japan

• SBM frequency (no./wk)

• SBM ≤ 24 h

• Time to first SBM

• Responder rate

Week 2

SBM frequency, mean (SD)

• Baseline: 2.86 (1.77)

• Elob: 6.08 (4.65); p < 0.001

Subgroup

Age: ≤74 years:

• Baseline: 2.82 (1.85)

• Elob: 6.31 (4.77); p < 0.001

Age: ≥75 years:

• Baseline: 2.90 (1.68)

• Elob: 5.82 (4.54); p < 0.001

SBM ≤ 24 h (%):

• Overall: 78.7%

• Aged ≤ 74 years: 78.3%; p = 0.92

• Aged ≥ 75 years: 79.3%; p = 0.92

Time to first SBM, mean (SD)

• Week 2: 14.8 (12.6) hrs

Responder rate, (n%):

• Week 2: 74%

Kumagai, 2018

Elobixibat

• Population: Adult

• Population type: CC

• Design: RCT, phase I (dose-escalating design)

• Sample size: 120

• Region: Japan

• SBM ≤ 24 h

Week 2

SBM ≤ 24 h (%)

• Elob 10 mg/day: 100%

• Elob 15 mg/day: 88.9%

• PBO: 40%

The time to the first SBM was shorter in the Elob groups than in the PBO

Nakajima, 2018b

Elobixibat

• Population: Adult

• Population type: CC plus IBS-C

• Design: RCT, phase IIb (JapicCTI-142,608)

• Sample size: 163

• Region: Japan

• Change from baseline in SBM frequency (no./wk)

• SBM ≤ 24 h

• Time to first SBM

SBM frequency, mean at baseline

• 1.6 to 1.8

Week 1

Change from baseline in SBM frequency, mean

• Elob 10 mg: 5.7; (p < 0.001, vs. PBO)

• Elob 15 mg: 5.6; (p < 0.001, vs. PBO)

• PBO: 2.6

SBM ≤ 24 h (%):

• Elob 10 mg: 90%; (p < 0.001, vs. PBO)

• Elob 15 mg: 93%; (p < 0.001, vs. PBO)

• PBO: 48%

Time to first SBM, mean

• Elob 10 mg: 8.2 h

• Elob 15 mg: 8.5 h

• PBO: 36.2 h

Nakajima, 2018a

Elobixibat

• Population: Adult

• Population type: CC plus IBS-C

• Design: RCT, phase III, (JapicCTI-153,061)

• Sample size: 132

• Region: Japan

• Change from baseline in SBM frequency (no./wk)

• SBM ≤ 24 h

• Responder rate (> 3 SBMs/wk)

Change from baseline in SBM frequency, LS mean (SE), [95% CI]

Week 1

• Elob 10 mg: 6·4 (0·6) [5.3–7.6]

• PBO: 1.7 (0.2) [1.2–2]

• Difference: 4.7(0.6) [3.4–5.9]; p < 0.0001

Week 2

• Elob 10 mg: 5.0 (0.4) [4.2–5.8]

• PBO: 1.8 (0.2) [1.3–2.2]

• Difference: 3.2(0.5) [2.3–4.1]; p < 0.0001

SBM ≤ 24 h (n %)

• Elob 10 mg: 86%

• PBO: 41%

• Difference: 44%; p < 0.0001

Responder rate (%)

Week 1

• Elob 10 mg: 94%

• PBO: 60%

• Difference: 34%

Week 2; p < 0.0001

• Elob 10 mg: 92%

• PBO: 63%

• Difference: 29%; p < 0.0001

Chey, 2011

Elobixibat

• Population: Adults

• Population type: CIC

• Design: RCT; phase IIb (NCT01007123)

• Sample size: 190

• Region: USA

• Change from baseline in SBM frequency (no./wk)

• SBM ≤ 24 h

• Time to first SBM

Change from baseline in SBM frequency, LS mean (95% CI)

Week 1

• Elob 10 mg: 4.0 (2.9–5.0); p < 0.002

• Elob 15 mg: 5.4 (4.4–6.4); p < 0.001

• PBO: 1.7 (0.7–2.8)

SBM ≤ 24 h (%):

• Elob 10 mg: 74%, (p = 0.012, vs. PBO)

• Elob 15 mg: 75%, (p = 0.012, vs. PBO)

• PBO: 45%

Time to first SBM, mean

• Elob 10 mg: 12 h (p = 0.033, vs. PBO)

• Elob 15 mg: 07 h (p = 0.039, vs. PBO)

• PBO: 27 h