A Phase 3, International, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Trial of Linaclotide Administered Orally for 12 Weeks to Patients With Irritable Bowel Syndrome With Constipation (IBS-C)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01880424

Acronym

D5630C00001

Enrollment

1722

Registered

2013-06-19

Start date

2013-07-31

Completion date

2015-05-31

Last updated

2016-09-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Irritable Bowel Syndrome With Constipation (IBS-C)

Brief summary

This clinical trial is an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial comparing one dose of linaclotide to placebo. Approximately 800 patients with a diagnosis of IBS-C (modified Rome III criteria) will be randomized at up to 60 trial centers in China, Australia, and New Zealand. The trial will consist of up to 21 days of screening, 14 to 21 days of pre-treatment, 12 weeks of double-blind treatment, and 2 weeks of follow-up. At the end of the Pre-treatment Period, patients meeting the entry criteria for this trial will be randomized to one of two double-blind treatment groups: 290 ug linaclotide, or placebo (1:1).

Interventions

DRUGPlacebo

matching Placebo Capsules, Oral, once daily

DRUGLinaclotide

Linaclotide 290 ug Capsules, Oral, once daily

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Patient has signed an Informed Consent Form(ICF). 2. Patient Must not be pregnant or breastfeeding and agree to use birth control 3. Patient meets the colonoscopy requirements defined by the American Gastroenterological Association guidelines and no clinically-significant laboratory or physical examination findings; 4. Patient meets protocol-defined criteria for Irritable Bowel Syndrome with Constipation(IBS-C), including stool frequency, straining, stool consistency, abdominal pain, and abdominal discomfort criteria 5. Patient meets protocol-defined eDiary completion Compliance and agrees to refrain from making any new, major life-style changes that may affect IBS-C symptoms

Exclusion criteria

1. Recent history of mushy or watery stools 2. Various medical conditions, medical histories, or family medical histories that would not make the patient a good candidate for the study 3. Patient currently has both unexplained and clinically significant alarm symptoms or systemic signs of infection or colitis. 4. Surgery to the gastrointestinal tract 5. Usage of prohibited medications

Design outcomes

Primary

Measure	Time frame	Description
12-week Abdominal Pain/Abdominal Discomfort Weekly Responder	Baseline and Weeks 1-12 during the Treatment Period	A 12-week Abdominal Pain/Abdominal Discomfort Responder is a patient who meets the Abdominal Pain/Abdominal Discomfort Weekly Responder criteria (i.e., an improvement of ≥30% from baseline in either the mean abdominal pain score or mean abdominal discomfort score for that week, with neither score worsening from baseline for that week) for at least 6 out of the 12 weeks of the Treatment Period. Abdominal pain at its worst (in the last 24 hours) was assessed daily by patients on an 11-point numerical rating scale (NRS) where 0 represents no abdominal pain and 10 represents very severe abdominal pain. Abdominal discomfort (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal discomfort and 10 represents very severe abdominal discomfort.
12-week Irritable Bowel Syndrome (IBS) Degree of Relief Responder	Baseline and Weeks 1-12 during the Treatment Period	A 12-week IBS Degree of Relief Responder is a patient who meets the IBS Degree of Relief Weekly Responder criteria (i.e., response to the degree of relief of IBS symptoms question for that week was Considerably relieved or Completely relieved) for at least 6 out of the 12 weeks of the Treatment Period. Degree of relief of IBS symptoms (in the last 7 days) was assessed weekly by patients on a 7-point balanced ordinal scale where 1 = Completely relieved, 4 = Unchanged, and 7 = As bad as I can imagine.

Secondary

Measure	Time frame	Description
Change From Baseline in 12-week Stool Consistency	Baseline and 12-week Treatment Period	The change from baseline in 12-week stool consistency (i.e., the average of the non-missing Bristol Stool Form Scale \[BSFS\] score from the SBMs occurring during the 12-week Treatment Period). Consistency of each bowel movement was assessed daily by patients using the 7-point BSFS (1=Separate hard lumps like nuts \[difficult to pass\] to 7=Watery, no solid pieces \[entirely liquid\]).
Change From Baseline in 12-week Severity of Straining	Baseline and 12-week Treatment Period	The change from baseline in 12-week severity of straining (i.e., the average of the non-missing straining scores from the SBMs occurring during the 12-week Treatment Period). Severity of straining was assessed daily by patients on a 5-point ordinal scale (1=Not at all to 5=An extreme amount).
Change From Baseline in 12-week Complete Spontaneous Bowel Movement Frequency Rate	Baseline and 12-week Treatment Period	The change from baseline in 12-week CSBM frequency (i.e., average weekly CSBM frequency over the 12 weeks of the Treatment Period). A spontaneous bowel movement (SBM) is defined as a bowel movement without laxative use in the preceding 24 hours. A CSBM is defined as an SBM that is associated with a sense of complete evacuation.
Change From Baseline in 12-week Abdominal Pain	Baseline and 12-week Treatment Period	The change from baseline in 12-week abdominal pain (i.e., the average of the non-missing daily abdominal pain scores reported during the 12-week Treatment Period). Abdominal pain at its worst (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal pain and 10 represents very severe abdominal pain.
Change From Baseline in 12-week Abdominal Discomfort	Baseline and 12-week Treatment Period	The change from baseline in 12-week abdominal discomfort (i.e., the average of the non-missing daily abdominal discomfort scores reported during the 12-week Treatment Period). Abdominal discomfort (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal discomfort and 10 represents very severe abdominal discomfort.
Change From Baseline in 12-week Abdominal Bloating	Baseline and 12-week Treatment Period	The change from baseline in 12-week abdominal bloating (i.e., the average of the non-missing daily abdominal bloating scores reported during the 12-week Treatment Period). Abdominal bloating (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating.
Change From Baseline in 12-week Spontaneous Bowel Movement Frequency Rate	Baseline and 12-week Treatment Period	The change from baseline in 12-week SBM frequency (i.e., average weekly SBM frequency over the 12 weeks of the Treatment Period). SBM is defined as a bowel movement without laxative use in the preceding 24 hours.

Countries

Australia, Canada, China, New Zealand, United States

Participant flow

Recruitment details

Patient recruitment occurred over an 18-month period from July 2013 to January 2015 at 98 study centers (40 in China, 42 in the US, 10 in Australia, 5 in New Zealand, and 1 in Canada).

Pre-assignment details

Patients went through a 14 to 21-day Pretreatment Period during which they provided qualifying bowel habit and symptom severity assessments and rescue medicine usage through an electronic diary (eDiary). 1722 patients provided consents with 839 qualified to join th study.

Participants by arm

Arm	Count
Linaclotide Arm Linaclotide 290 ug capsules, oral, once daily	417
Placebo Arm matching placebo capsules, oral, once daily	422
Total	839

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	7	6
Overall Study	Lack of Efficacy	1	4
Overall Study	Lost to Follow-up	3	2
Overall Study	Other	1	0
Overall Study	Protocol Violation	11	13
Overall Study	Withdrawal by Subject	10	30

Baseline characteristics

Characteristic	Placebo Arm	Total	Linaclotide Arm
Age, Continuous	41.3 years STANDARD_DEVIATION 13.5	41.1 years STANDARD_DEVIATION 13.3	41.0 years STANDARD_DEVIATION 13.1
Age, Customized >= 65 years	17 participants	34 participants	17 participants
Age, Customized between 18 to 65 years	405 participants	805 participants	400 participants
countries Australia	14 Participants	33 Participants	19 Participants
countries Canada	3 Participants	6 Participants	3 Participants
countries China	332 Participants	659 Participants	327 Participants
countries New Zealand	4 Participants	8 Participants	4 Participants
countries United States	69 Participants	133 Participants	64 Participants
Sex: Female, Male Female	355 Participants	688 Participants	333 Participants
Sex: Female, Male Male	67 Participants	151 Participants	84 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	56 / 416	26 / 419
serious Total, serious adverse events	4 / 416	10 / 419

Outcome results

Primary

12-week Abdominal Pain/Abdominal Discomfort Weekly Responder

A 12-week Abdominal Pain/Abdominal Discomfort Responder is a patient who meets the Abdominal Pain/Abdominal Discomfort Weekly Responder criteria (i.e., an improvement of ≥30% from baseline in either the mean abdominal pain score or mean abdominal discomfort score for that week, with neither score worsening from baseline for that week) for at least 6 out of the 12 weeks of the Treatment Period. Abdominal pain at its worst (in the last 24 hours) was assessed daily by patients on an 11-point numerical rating scale (NRS) where 0 represents no abdominal pain and 10 represents very severe abdominal pain. Abdominal discomfort (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal discomfort and 10 represents very severe abdominal discomfort.

Time frame: Baseline and Weeks 1-12 during the Treatment Period

Population: Intent to Treat (ITT) Population (all 839 randomized patients). If a patient did not have an abdominal pain score or abdominal discomfort score for a particular Treatment Period week, the patient was not considered a responder for that week.

Arm	Measure	Value (NUMBER)
Linaclotide Arm	12-week Abdominal Pain/Abdominal Discomfort Weekly Responder	250 Participants
Placebo Arm	12-week Abdominal Pain/Abdominal Discomfort Weekly Responder	206 Participants

Comparison: Null Hypothesis: There is no difference between the linaclotide dose and placebo in the proportion of 12-week Abdominal Pain/Abdominal Discomfort Responders or there is no difference in the proportion of 12-week IBS Degree of Relief Responders. With 800 planned patients, the statistical power was expected to be approximately 95%, with an overall type I error rate controlled at the 0.05 level (2-sided), based on assumptions from NCT00948818 (LIN-MD-31) study data.p-value: 0.00195% CI: [1.21, 2.09]Cochran-Mantel-Haenszel

Primary

12-week Irritable Bowel Syndrome (IBS) Degree of Relief Responder

A 12-week IBS Degree of Relief Responder is a patient who meets the IBS Degree of Relief Weekly Responder criteria (i.e., response to the degree of relief of IBS symptoms question for that week was Considerably relieved or Completely relieved) for at least 6 out of the 12 weeks of the Treatment Period. Degree of relief of IBS symptoms (in the last 7 days) was assessed weekly by patients on a 7-point balanced ordinal scale where 1 = Completely relieved, 4 = Unchanged, and 7 = As bad as I can imagine.

Time frame: Baseline and Weeks 1-12 during the Treatment Period

Population: Intent to Treat (ITT) Population (all 839 randomized patients). If a patient did not have an IBS degree of relief score for a particular Treatment Period week, the patient was not considered a responder for that week.

Arm	Measure	Value (NUMBER)
Linaclotide Arm	12-week Irritable Bowel Syndrome (IBS) Degree of Relief Responder	132 Participants
Placebo Arm	12-week Irritable Bowel Syndrome (IBS) Degree of Relief Responder	65 Participants

Secondary

Change From Baseline in 12-week Abdominal Bloating

The change from baseline in 12-week abdominal bloating (i.e., the average of the non-missing daily abdominal bloating scores reported during the 12-week Treatment Period). Abdominal bloating (in the last 24 hours) was assessed daily by patients on an 11-point NRS where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating.