Trial Outcomes & Findings for A Study of the Effect of Linaclotide on Abdominal Girth in Participants With Irritable Bowel Syndrome With Constipation (IBS-C) (NCT NCT02837783)

NCT ID: NCT02837783

Last Updated: 2021-12-06

Results Overview

Mean change in abdominal girth (physical measure of bloating/distension) as measured by area under the curve (AUC), determined by 24-hour abdominal inductance plesthymography (AIP; with hourly averages). The AUC was calculated using the Trapezoidal method from the first reliable hour of measurement to last measurement (bedtime). The AUC for each participant was then individually standardized by dividing the total AUC over the period by that patient's number of hours of measurement included in the AUC. (Therefore, the time element was removed from the standardized AUC, and the unit of measure for this outcome is centimeters \[cm\]).

• Recruitment status: TERMINATED
• Study phase: PHASE4
• Target enrollment: 20 participants
• Primary outcome timeframe: Baseline, Week 4
• Results posted on: 2021-12-06

Participant Flow

The study included a 14-day screening period and a 7 day pretreatment period. The treatment period began with randomization and lasted for 4 weeks. Participants who met entry criteria were randomized (1:1) to once daily oral capsules containing 290 µg linaclotide or placebo.

Participant milestones

Measure	Matching Placebo Placebo once daily for 4 weeks	290 μg Linaclotide 290 µg linaclotide once daily for 4 weeks
Overall Study STARTED	9	11
Overall Study Received >= 1 Dose of Study Drug	9	10
Overall Study COMPLETED	7	9
Overall Study NOT COMPLETED	2	2

Reasons for withdrawal

Measure	Matching Placebo Placebo once daily for 4 weeks	290 μg Linaclotide 290 µg linaclotide once daily for 4 weeks
Overall Study Adverse Event	1	0
Overall Study Other, Not Specified	1	2

Baseline Characteristics

A Study of the Effect of Linaclotide on Abdominal Girth in Participants With Irritable Bowel Syndrome With Constipation (IBS-C)

Baseline characteristics by cohort

Measure	Matching Placebo n=9 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=11 Participants 290 μg linaclotide once daily for 4 weeks	Total n=20 Participants Total of all reporting groups
Age, Continuous	35.8 years STANDARD_DEVIATION 10.38 • n=5 Participants	35.2 years STANDARD_DEVIATION 12.82 • n=7 Participants	35.5 years STANDARD_DEVIATION 11.49 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	11 Participants n=7 Participants	20 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	9 Participants n=5 Participants	11 Participants n=7 Participants	20 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	9 Participants n=5 Participants	11 Participants n=7 Participants	20 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 4

Population: Participants with an assessment at given time point.

Mean change in abdominal girth (physical measure of bloating/distension) as measured by area under the curve (AUC), determined by 24-hour abdominal inductance plesthymography (AIP; with hourly averages). The AUC was calculated using the Trapezoidal method from the first reliable hour of measurement to last measurement (bedtime). The AUC for each participant was then individually standardized by dividing the total AUC over the period by that patient's number of hours of measurement included in the AUC. (Therefore, the time element was removed from the standardized AUC, and the unit of measure for this outcome is centimeters [cm]).

Outcome measures

Measure	Matching Placebo n=9 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=11 Participants 290 μg linaclotide once daily for 4 weeks
Change From Baseline in Abdominal Girth at Week 4 Baseline	82.6 cm Standard Deviation 11.8	83.7 cm Standard Deviation 9.02
Change From Baseline in Abdominal Girth at Week 4 Change From Baseline	-3.36 cm Standard Deviation 4.04	-0.632 cm Standard Deviation 11.6

SECONDARY outcome

Timeframe: Baseline, Week 2

Population: Participants with an assessment at given time point.

Mean change in abdominal girth (physical measure of bloating/distention) as measured by AUC, determined by 24-hour AIP (with hourly averages). The AUC was calculated using the Trapezoidal method from the first reliable hour of measurement to last measurement (bedtime). The AUC for each participant was then individually standardized by dividing the total AUC over the period by that patient's number of hours of measurement included in the AUC. (Therefore, the time element was removed from the standardized AUC, and the unit of measure for this outcome is centimeters [cm]).

Outcome measures

Measure	Matching Placebo n=8 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=10 Participants 290 μg linaclotide once daily for 4 weeks
Change From Baseline in Abdominal Girth at Week 2	0.535 cm Standard Deviation 9.15	-2.3 cm Standard Deviation 13.7

SECONDARY outcome

Timeframe: Baseline, Week 4

Population: Participants with an assessment at given time point.

The maximum change in girth from the first hour, over the period from the 2nd hour to bedtime. The percentage change in maximum distension from baseline to 4 weeks will also be calculated.

Outcome measures

Measure	Matching Placebo n=7 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=9 Participants 290 μg linaclotide once daily for 4 weeks
Percent Change From Baseline in Maximal Abdominal Girth at Week 4	-7.13 percent change Standard Deviation 33.4	15.4 percent change Standard Deviation 80.3

SECONDARY outcome

Timeframe: Baseline, Week 1

Population: Participants with an assessment at given time point.

Symptom severity was assessed daily on an 11-point numerical rating scale (NRS) from 0 to 10, where 0 represents no symptoms and 10 represents very severe symptoms. Participants rated their abdominal pain, discomfort, bloating, and distension at its worst over the last 24 hours. Weekly average scores were calculated individually for abdominal pain, discomfort, bloating, distension. The abdominal score was calculated as the weekly average from the daily scores of the individual items of pain, discomfort, bloating combined. The abdominal score plus distension was calculated as the weekly average from the daily scores of the individual items of pain, discomfort, bloating and distension combined.

Outcome measures

Measure	Matching Placebo n=8 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=11 Participants 290 μg linaclotide once daily for 4 weeks
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 1 Pain	-1.25 units on a scale Standard Deviation 1.76	-0.75 units on a scale Standard Deviation 1.88
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 1 Discomfort	-1.93 units on a scale Standard Deviation 1.54	-0.97 units on a scale Standard Deviation 2.05
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 1 Bloating	-2.00 units on a scale Standard Deviation 1.48	-0.40 units on a scale Standard Deviation 1.23
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 1 Distension	-1.91 units on a scale Standard Deviation 1.41	-0.15 units on a scale Standard Deviation 1.02
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 1 Abdominal Score	-1.73 units on a scale Standard Deviation 1.50	-0.71 units on a scale Standard Deviation 1.58
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 1 Abdominal Score + Distension	-1.77 units on a scale Standard Deviation 1.43	-0.57 units on a scale Standard Deviation 1.36

SECONDARY outcome

Timeframe: Baseline, Week 2

Population: Participants with an assessment at given time point.

Symptom severity was assessed daily on an 11-point NRS from 0 to 10, where 0 represents no symptoms and 10 represents very severe symptoms. Participants rated their abdominal pain, discomfort, bloating, and distension at its worst over the last 24 hours. Weekly average scores were calculated individually for abdominal pain, discomfort, bloating, distension. The abdominal score was calculated as the weekly average from the daily scores of the individual items of pain, discomfort, bloating combined. The abdominal score plus distension was calculated as the weekly average from the daily scores of the individual items of pain, discomfort, bloating and distension combined.

Outcome measures

Measure	Matching Placebo n=8 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=10 Participants 290 μg linaclotide once daily for 4 weeks
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 2 Pain	-1.97 units on a scale Standard Deviation 1.60	-1.42 units on a scale Standard Deviation 1.88
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 2 Discomfort	-2.51 units on a scale Standard Deviation 1.15	-1.73 units on a scale Standard Deviation 2.27
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 2 Bloating	-2.65 units on a scale Standard Deviation 1.30	-1.04 units on a scale Standard Deviation 1.54
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 2 Distension	-2.51 units on a scale Standard Deviation 1.37	-0.78 units on a scale Standard Deviation 1.33
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 2 Abdominal Score	-2.38 units on a scale Standard Deviation 1.19	-1.40 units on a scale Standard Deviation 1.69
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 2 Abdominal Score + Distension	-2.41 units on a scale Standard Deviation 1.18	-1.25 units on a scale Standard Deviation 1.52

SECONDARY outcome

Timeframe: Baseline, Week 3

Population: Participants with an assessment at given time point.

Symptom severity was assessed daily on an 11-point NRS from 0 to 10, where 0 represents no symptoms and 10 represents very severe symptoms. Participants rated their abdominal pain, discomfort, bloating, and distension at its worst over the last 24 hours. Weekly average scores were calculated individually for abdominal pain, discomfort, bloating, distension. The abdominal score was calculated as the weekly average from the daily scores of the individual items of pain, discomfort, bloating combined. The abdominal score plus distension was calculated as the weekly average from the daily scores of the individual items of pain, discomfort, bloating and distension combined.

Outcome measures

Measure	Matching Placebo n=8 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=10 Participants 290 μg linaclotide once daily for 4 weeks
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 3 Pain	-1.60 units on a scale Standard Deviation 2.66	-2.07 units on a scale Standard Deviation 1.88
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 3 Discomfort	-2.01 units on a scale Standard Deviation 1.86	-2.25 units on a scale Standard Deviation 2.26
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 3 Bloating	-2.02 units on a scale Standard Deviation 1.67	-1.16 units on a scale Standard Deviation 1.51
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 3 Distension	-1.79 units on a scale Standard Deviation 1.80	-1.05 units on a scale Standard Deviation 1.37
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 3 Abdominal Score	-1.88 units on a scale Standard Deviation 1.95	-1.82 units on a scale Standard Deviation 1.64
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 3 Abdominal Score + Distension	-1.86 units on a scale Standard Deviation 1.87	-1.64 units on a scale Standard Deviation 1.46

SECONDARY outcome

Timeframe: Baseline, Week 4

Population: Participants with an assessment at given time point.

Symptom severity was assessed daily on an 11-point NRS from 0 to 10, where 0 represents no symptoms and 10 represents very severe symptoms. Participants rated their abdominal pain, discomfort, bloating, and distension at its worst over the last 24 hours. Weekly average scores were calculated individually for abdominal pain, discomfort, bloating, distension. The abdominal score was calculated as the weekly average from the daily scores of the individual items of pain, discomfort, bloating combined. The abdominal score plus distension was calculated as the weekly average from the daily scores of the individual items of pain, discomfort, bloating and distension combined.

Outcome measures

Measure	Matching Placebo n=8 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=10 Participants 290 μg linaclotide once daily for 4 weeks
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 4 Pain	-1.71 units on a scale Standard Deviation 2.44	-1.90 units on a scale Standard Deviation 1.50
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 4 Discomfort	-1.94 units on a scale Standard Deviation 1.63	-2.24 units on a scale Standard Deviation 1.92
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 4 Bloating	-1.84 units on a scale Standard Deviation 1.64	-1.64 units on a scale Standard Deviation 1.74
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 4 Distension	-1.70 units on a scale Standard Deviation 1.60	-1.22 units on a scale Standard Deviation 1.69
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 4 Abdominal Score	-1.83 units on a scale Standard Deviation 1.84	-1.91 units on a scale Standard Deviation 1.39
Change From Baseline of Symptom Severity (Abdominal Pain, Discomfort, Bloating, and Distension) at Week 4 Abdominal Score + Distension	-1.80 units on a scale Standard Deviation 1.75	-1.74 units on a scale Standard Deviation 1.37

SECONDARY outcome

Timeframe: Baseline, Week 2

Population: Participants with an assessment at given time point.

A digestive sensations questionnaire was used to record abdominal pain, discomfort, bloating, and distension symptoms on an hourly basis (waking hours only) during the 24 hours the participants are fitted with the AIP belt, using an 11-point NRS, with 0=no symptomatic sensations and 10=most severe symptomatic sensations. Daily diary scores for each of the digestive symptoms was averaged to obtain 'weekly' scores.

Outcome measures

Measure	Matching Placebo n=8 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=10 Participants 290 μg linaclotide once daily for 4 weeks
Change From Baseline in Digestive Sensations (Subjective Bloating, Abdominal Discomfort, Abdominal Distension and Abdominal Pain) at Week 2 Pain	-1.13 units on a scale Standard Deviation 1.38	-0.61 units on a scale Standard Deviation 1.10
Change From Baseline in Digestive Sensations (Subjective Bloating, Abdominal Discomfort, Abdominal Distension and Abdominal Pain) at Week 2 Discomfort	-1.01 units on a scale Standard Deviation 1.53	-1.00 units on a scale Standard Deviation 1.34
Change From Baseline in Digestive Sensations (Subjective Bloating, Abdominal Discomfort, Abdominal Distension and Abdominal Pain) at Week 2 Bloating	-1.03 units on a scale Standard Deviation 1.54	-0.58 units on a scale Standard Deviation 1.33
Change From Baseline in Digestive Sensations (Subjective Bloating, Abdominal Discomfort, Abdominal Distension and Abdominal Pain) at Week 2 Distension	-0.97 units on a scale Standard Deviation 1.50	-0.36 units on a scale Standard Deviation 1.14

SECONDARY outcome

Timeframe: Baseline, Week 4

Population: Participants with an assessment at given time point.

A digestive sensations questionnaire was used to record abdominal pain, discomfort, bloating, and distension on an hourly basis (waking hours only) during the 24 hours the participants are fitted with the AIP belt, using an 11-point NRS, with 0=no symptomatic sensations and 10=most severe symptomatic sensations. Daily diary scores for each of the digestive symptoms was averaged to obtain 'weekly' scores.

Outcome measures

Measure	Matching Placebo n=7 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=9 Participants 290 μg linaclotide once daily for 4 weeks
Change From Baseline in Digestive Sensations (Subjective Bloating, Abdominal Discomfort, Abdominal Distension and Abdominal Pain) at Week 4 Pain	-0.97 units on a scale Standard Deviation 1.55	-0.87 units on a scale Standard Deviation 1.33
Change From Baseline in Digestive Sensations (Subjective Bloating, Abdominal Discomfort, Abdominal Distension and Abdominal Pain) at Week 4 Discomfort	-0.89 units on a scale Standard Deviation 1.51	-1.81 units on a scale Standard Deviation 1.11
Change From Baseline in Digestive Sensations (Subjective Bloating, Abdominal Discomfort, Abdominal Distension and Abdominal Pain) at Week 4 Bloating	-1.01 units on a scale Standard Deviation 1.57	-1.66 units on a scale Standard Deviation 1.03
Change From Baseline in Digestive Sensations (Subjective Bloating, Abdominal Discomfort, Abdominal Distension and Abdominal Pain) at Week 4 Distension	-1.03 units on a scale Standard Deviation 1.49	-1.42 units on a scale Standard Deviation 0.64

SECONDARY outcome

Timeframe: Baseline, Week 1, Week 2, Week 3, Week 4

Population: Participants with an assessment at given time point.

Daily stool consistency analyses were performed using the 7-point Bristol Stool Form Scale (BSFS), whereby a score of 1 = separate hard lumps like nuts (difficult to pass); 2 = sausage shaped but lumpy; 3 = like a sausage but with cracks on surface; 4 = like a sausage or snake, smooth and soft; 5 = soft blobs with clear-cut edges (passed easily); 6 = fluffy pieces with ragged edges, a mushy stool; and 7 = watery, no solid pieces (entirely liquid). Daily average recorded BSFS scores for each participant were computed for each week.

Outcome measures

Measure	Matching Placebo n=8 Participants Placebo once daily for 4 weeks	290 μg Linaclotide n=11 Participants 290 μg linaclotide once daily for 4 weeks
Change From Baseline in Bristol Stool Form Scale (BSFS) Over Time Week 1	0.33 score on a scale Standard Deviation 0.88	1.53 score on a scale Standard Deviation 1.57
Change From Baseline in Bristol Stool Form Scale (BSFS) Over Time Week 2	0.57 score on a scale Standard Deviation 0.86	1.51 score on a scale Standard Deviation 1.27
Change From Baseline in Bristol Stool Form Scale (BSFS) Over Time Week 3	0.39 score on a scale Standard Deviation 1.15	2.11 score on a scale Standard Deviation 1.43
Change From Baseline in Bristol Stool Form Scale (BSFS) Over Time Week 4	0.35 score on a scale Standard Deviation 1.11	1.56 score on a scale Standard Deviation 1.13

Adverse Events

Matching Placebo

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

290 μg Linaclotide

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Measure	Matching Placebo n=9 participants at risk Placebo once daily for 4 weeks	290 μg Linaclotide n=10 participants at risk 290 μg linaclotide once daily for 4 weeks
Nervous system disorders Loss of consciousness	11.1% 1/9 • From first dose of study drug through Day 36 (± 2 days).	0.00% 0/10 • From first dose of study drug through Day 36 (± 2 days).

Other adverse events

Measure	Matching Placebo n=9 participants at risk Placebo once daily for 4 weeks	290 μg Linaclotide n=10 participants at risk 290 μg linaclotide once daily for 4 weeks
Gastrointestinal disorders Abdominal pain	0.00% 0/9 • From first dose of study drug through Day 36 (± 2 days).	10.0% 1/10 • From first dose of study drug through Day 36 (± 2 days).
Gastrointestinal disorders Abdominal pain upper	0.00% 0/9 • From first dose of study drug through Day 36 (± 2 days).	10.0% 1/10 • From first dose of study drug through Day 36 (± 2 days).
Gastrointestinal disorders Anal haemorrhage	0.00% 0/9 • From first dose of study drug through Day 36 (± 2 days).	10.0% 1/10 • From first dose of study drug through Day 36 (± 2 days).
Gastrointestinal disorders Diarrhoea	0.00% 0/9 • From first dose of study drug through Day 36 (± 2 days).	50.0% 5/10 • From first dose of study drug through Day 36 (± 2 days).
Gastrointestinal disorders Nausea	0.00% 0/9 • From first dose of study drug through Day 36 (± 2 days).	10.0% 1/10 • From first dose of study drug through Day 36 (± 2 days).
Injury, poisoning and procedural complications Back injury	11.1% 1/9 • From first dose of study drug through Day 36 (± 2 days).	0.00% 0/10 • From first dose of study drug through Day 36 (± 2 days).
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.00% 0/9 • From first dose of study drug through Day 36 (± 2 days).	10.0% 1/10 • From first dose of study drug through Day 36 (± 2 days).

Additional Information

Lara Lane

Ironwood Pharmaceuticals, Inc.

Phone: (617) 621-7722

Email: llane@ironwoodpharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee PI may publish or disclose the results of the study 24 months after final data lock provided that sponsor can review the publication prior to public release, sponsor can request removal of confidential information of sponsor (not including results of trial), and sponsor can request a publication delay in order to protect potentially patentable information. Furthermore, if a publication committee is developing an initial publication, PI is to delay disclosure until that publication is published.
• Publication restrictions are in place

Restriction type: OTHER