Trial of Linaclotide Administered to Patients With Irrita... | NCT00948818

Status Module

Name	Class
Ironwood Pharmaceuticals, Inc.	INDUSTRY

Label	Type	Description	Intervention Names
Linaclotide	Experimental	Linaclotide 290 micrograms	Drug: Linaclotide 290 micrograms
Placebo	Placebo Comparator	Matching placebo	Drug: Matching placebo

Name	Type	Description	Arm Group Labels	Other Names
Linaclotide 290 micrograms	Drug	Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study	Linaclotide

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 9 Out of 12 Weeks	A patient is considered to be an APC responder if, for at least 9 out of the 12 weeks of the treatment period, the patient had at least 3 CSBMs, experienced an increase of at least 1 CSBM from baseline, and experienced a decrease of at least 30 percent in their Abdominal Pain (AP) score from baseline during a particular week. The AP score assesses the worst of a patient's AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP. A CSBM is defined as a spontaneous bowel movement, associated with a sense of complete evacuation.	Change from Baseline to Week 12
Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder, 9 Out of 12 Weeks	A patient is considered to be a CSBM 3+1 responder if, for at least 9 out of the 12 weeks of the treatment period, the patient had at least 3 CSBMs and experienced an increase of at least 1 CSBM from baseline during a particular week. A CSBM was defined as a Spontaneous Bowel Movement (SBM) that was associated with a sense of complete evacuation. An SBM was defined as a bowel movement (BM) that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.	Change from Baseline to Week 12
Abdominal Pain Responder, 9 Out of 12 Weeks	A patient is considered to be an abdominal pain responder if, for at least 9 out of the 12 weeks of the treatment period, they experienced a decrease of at least 30 percent in the mean abdominal pain score from baseline during a particular week. The Abdominal Pain score assesses the worst of a patient's abdominal pain in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no abdominal pain and 10 represents very severe abdominal pain.	Change from Baseline to Week 12
Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 6 Out of 12 Weeks.	A patient is considered an APC responder if, for at least 6 of the 12 weeks of the treatment, the patient experienced an increase of at least 1 Complete Spontaneous Bowel Movement (CSBM) from baseline and experienced a decrease of at least 30 percent in their Abdominal Pain (AP)score during a particular week. The AP score assesses the worst of a patient's AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP. A CSBM was defined as a Spontaneous Bowel Movement (SBM) that was associated with a sense of complete evacuation.

Secondary Outcomes

Measure	Description	Time Frame
12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate	The number of CSBMs per week.	Change from Baseline to Week 12
12-Week Spontaneous Bowl Movement (SBM) Frequency Rate	The number of Spontaneous Bowl Movements experienced per week.

Eligibility Module

Name	Affiliation	Role
Paul F.C. Eng, PhD	Forest Research Institute, a subsidiary of Forest Laboratories Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Forest Investigative Site 037		Birmingham	Alabama	35209	United States
Forest Investigative Site 036

PubMed Identifier	Type	Citation	Retractions
24075889	Derived	Rao SS, Quigley EM, Shiff SJ, Lavins BJ, Kurtz CB, MacDougall JE, Currie MG, Johnston JM. Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation. Clin Gastroenterol Hepatol. 2014 Apr;12(4):616-23. doi: 10.1016/j.cgh.2013.09.022. Epub 2013 Sep 25.
23116208	Derived

Results Section

Participant Flow Module

ID	Title	Description
FG000	Placebo	Dose-matched placebo, oral administration, once per day.
FG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 9 Out of 12 Weeks

A patient is considered to be an APC responder if, for at least 9 out of the 12 weeks of the treatment period, the patient had at least 3 CSBMs, experienced an increase of at least 1 CSBM from baseline, and experienced a decrease of at least 30 percent in their Abdominal Pain (AP) score from baseline during a particular week.

The AP score assesses the worst of a patient's AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP.

A CSBM is defined as a spontaneous bowel movement, associated with a sense of complete evacuation.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the Intent to Treat (ITT) Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Number

Participants

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants	OG000395 OG001405

Title

Denominators

Categories

Responder

Title	Measurements
	OG00020 OG00149

Nonresponder

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Null Hypothesis: There is no difference between the 290 μg dose and placebo groups in the proportion of 9/12 Week APC 3 + 1 Responders. The power, adjusted for multiplicity, was expected to be 93% based on NCT00460811 (MCP-103-202) study data.	Cochran-Mantel-Haenszel		0.0004	The p-value is still less than 0.05 after adjusting multiplicity using a serial gatekeeping multiple comparison procedure.	Odds Ratio (OR)	2.60			2-Sided	95	1.51	4.47				No	Superiority or Other

Secondary

12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate

The number of CSBMs per week.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Least Squares Mean

Standard Error

CSBMs per Week

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants	OG000

Primary

Complete Spontaneous Bowel Movement (CSBM) 3+1 Responder, 9 Out of 12 Weeks

A patient is considered to be a CSBM 3+1 responder if, for at least 9 out of the 12 weeks of the treatment period, the patient had at least 3 CSBMs and experienced an increase of at least 1 CSBM from baseline during a particular week.

A CSBM was defined as a Spontaneous Bowel Movement (SBM) that was associated with a sense of complete evacuation.

An SBM was defined as a bowel movement (BM) that occurred in the absence of laxative, enema, or suppository use on either the calendar day of the BM or the calendar day before the BM.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Number

Participant

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts

Primary

Abdominal Pain Responder, 9 Out of 12 Weeks

A patient is considered to be an abdominal pain responder if, for at least 9 out of the 12 weeks of the treatment period, they experienced a decrease of at least 30 percent in the mean abdominal pain score from baseline during a particular week.

The Abdominal Pain score assesses the worst of a patient's abdominal pain in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no abdominal pain and 10 represents very severe abdominal pain.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Number

Participants

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants

Primary

Abdominal Pain and Complete Spontaneous Bowel Movement (APC) Responder, 6 Out of 12 Weeks.

A patient is considered an APC responder if, for at least 6 of the 12 weeks of the treatment, the patient experienced an increase of at least 1 Complete Spontaneous Bowel Movement (CSBM) from baseline and experienced a decrease of at least 30 percent in their Abdominal Pain (AP)score during a particular week.

The AP score assesses the worst of a patient's AP in the past 24 hours using an 11-point scale (from 0-10), where 0 represents no AP and 10 represents very severe AP.

A CSBM was defined as a Spontaneous Bowel Movement (SBM) that was associated with a sense of complete evacuation.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Number

Participants

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Secondary

12-Week Spontaneous Bowl Movement (SBM) Frequency Rate

The number of Spontaneous Bowl Movements experienced per week.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Least Squares Mean

Standard Error

SBMs per week

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants	OG000

Secondary

12-Week Stool Consistency

The consistency of each BM was assessed by patients using the 7-point Bristol Stool Form Scale (BSFS) from 1 to 7.

= separate hard lumps like nuts [difficult to pass]
= sausage shaped but lumpy
= like a sausage but with cracks on surface
= like a sausage or snake, smooth and soft
= soft blobs with clear-cut edges [passed easily]
= fluffy pieces with ragged edges, a mushy stool
= watery, no solid pieces [entirely liquid]).

802 randomized patients received study drug. The 800 patients in the ITT population had at least 1 postrandomization entry of the primary efficacy assessment; 107 patients with no pretreatment spontaneous bowel movements were excluded from the 12-Week Stool Consistency analysis. An observed-cases approach to missing postbaseline data was applied.

Posted

Least Squares Mean

Standard Error

units on a scale

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants

Secondary

12-Week Severity of Straining

Straining is measured on a 5-point scale where a value of 1 is "not at all" and a value of 5 is "an extreme amount.

802 randomized patients received study drug. The 800 patients in the ITT population had at least 1 postrandomization entry of the primary efficacy assessment; 107 patients with no pretreatment spontaneous bowel movements were excluded from the Severity of Straining analysis. An observed-cases approach to missing postbaseline data was applied.

Posted

Least Squares Mean

Standard Error

units on a scale

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants	OG000

Secondary

12-Week Change in Abdominal Pain Score

Abdominal Pain at its worst (in the last 24 hours) is based on an 11-point scale where 0 represents no abdominal pain and 10 represents very severe abdominal pain.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Least Squares Mean

Standard Error

units on a scale

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants	OG000

Secondary

12-Week Change in Abdominal Discomfort

Abdominal Discomfort is measured on an 11-point scale where a value of 0 is "none" and a value of 10 is "very severe."

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Least Squares Mean

Standard Error

units on a scale

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants	OG000

Secondary

12-Week Change in Bloating

Bloating was assessed on an 11-point scale where a value of 0 is "none" and a value of 10 is "very severe".

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Least Squares Mean

Standard Error

units on a scale

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants	OG000

Secondary

Complete Spontaneous Bowl Movement (CSBM) Responder for 6 Weeks Out of 12 Weeks of Treatment

A patient is considered to be a CSBM responder if, for at least 6 out of the 12 weeks of the treatment period, an increase of at least 1 CSBM per week from baseline was experienced.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Number

Participants

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants	OG000

Secondary

Abdominal Pain Responder for 6 Out of 12 Weeks

A patient is considered to be an abdominal pain responder if, for at least 6 out of the 12 weeks of the treatment period, they experienced a decrease of 30 percent or more in the abdominal pain score from baseline.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Number

Participants

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants

Secondary

12-Week Percent of Abdominal Pain-free (APF) Days

Abdominal pain free (APF) days are those days where the patient reported a score of '0' for abdominal pain at its worst

Abdominal Pain at its worst (in the last 24 hours) is based on an 11-point scale where 0 represents no abdominal pain and 10 represents very severe abdominal pain.

803 patients were randomized to treatment, and 802 patients received double-blind study drug. 800 patients had at least 1 postrandomization entry of the primary efficacy assessment and were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.

Posted

Mean

Standard Deviation

Percent

Change from Baseline to Week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.

Units	Counts
Participants	OG000

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo - Treatment Period	Dose-matched placebo, oral administration, once per day.	2	396	22	396
EG001	Linaclotide - Treatment Period	Linaclotide 290µg, oral administration, once per day.	2	406	93	406
EG002	Placebo to Linaclotide - Randomized Withdrawal Period	Linaclotide 290µg, oral administration, once per day during a 4-week randomized withdrawal period. This group had previously received dose-matched placebo during the 12-week randomized treatment period.	0	333	41	333
EG003	Linaclotide to Placebo - Randomized Withdrawal Period	Dose-matched placebo, oral administration, once per day during a 4-week randomized withdrawal period. This group had previously received linaclotide 290µg, oral administration, once per day during the 12-week treatment period.	0	154	1	154
EG004	Linaclotide to Linaclotide - Randomized Withdrawal Period	Linaclotide 290µg, oral administration, once per day during a 4-week randomized withdrawal period	0	158	5	158

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected396 at risk EG0011 affected406 at risk EG0020 affected333 at risk EG0030 affected154 at risk EG0040 affected158 at risk
Pericardial effusion	Cardiac disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected396 at risk EG0011 affected406 at risk EG0020 affected333 at risk EG003
Pericarditis	Cardiac disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected396 at risk EG0011 affected406 at risk EG0020 affected333 at risk EG003
Cholecystitis chronic	Hepatobiliary disorders	MedDRA 13.0	Systematic Assessment	EG0001 affected396 at risk EG0010 affected406 at risk EG0020 affected333 at risk EG003
Duodenitis	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0001 affected396 at risk EG0010 affected406 at risk EG0020 affected333 at risk EG003
Gastroenteritis	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0001 affected396 at risk EG0010 affected406 at risk EG0020 affected333 at risk EG003
Hiatus hernia	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0001 affected396 at risk EG0010 affected406 at risk EG0020 affected333 at risk EG003
Oesophagitis	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0001 affected396 at risk EG0010 affected406 at risk EG0020 affected333 at risk EG003
Renal cyst	Renal and urinary disorders	MedDRA 13.0	Systematic Assessment	EG0001 affected396 at risk EG0010 affected406 at risk EG0020 affected333 at risk EG003
Urinary tract infection	Renal and urinary disorders	MedDRA 13.0	Systematic Assessment	EG0001 affected396 at risk EG0010 affected406 at risk EG0020 affected333 at risk EG003

ID	Term
D043183	Irritable Bowel Syndrome
D003248	Constipation

ID	Term
D003109	Colonic Diseases, Functional
D003108	Colonic Diseases
D007410	Intestinal Diseases
D005767	Gastrointestinal Diseases
D004066	Digestive System Diseases
D012817	Signs and Symptoms, Digestive
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms

ID	Title	Description
BG000	Placebo	Dose-matched placebo, oral administration, once per day.
BG001	Linaclotide	Linaclotide 290µg, oral administration, once per day.
BG002	Total	Total of all reporting groups

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Diarrhea	General disorders	MedDRA 13.0	Systematic Assessment		EG00014 affected396 at risk EG00179 affected406 at risk EG00239 affected333 at risk EG0031 affected154 at risk EG0043 affected158 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment		EG00010 affected396 at risk EG00122 affected406 at risk EG0028 affected333 at risk EG003