Chronic Constipation
Conditions
Brief summary
The objective of this trial is to determine the efficacy and safety of linaclotide administered to patients with chronic constipation (CC). The primary efficacy parameter is the percentage of patients in each dosing group that meet the protocol definition for Complete Spontaneous Bowel Movement (CSBM) Overall Responder.
Interventions
DRUGMatching Placebo
Oral, once daily
DRUGLinaclotide
Oral, once daily
Sponsors
Forest Laboratories
Ironwood Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient has completed a colonoscopy according to the AGA criteria, with no clinically significant findings * Patient has successfully completed protocol procedures (with no clinically significant findings): physical exam, 12-lead ECG, or clinical laboratory tests * Patient meets protocol criteria for CC: reports \< 3 bowel movements per week and reports straining, lumpy or hard stools, and/or sensation of incomplete evacuation during \> 25% of BMs * Patient demonstrates continued chronic constipation through Pretreatment Period * Patient is compliant with IVRS
Exclusion criteria
* Patient has history of loose or watery stools * Patient has symptoms of or been diagnosed with Irritable Bowel Syndrome (IBS) * Patient has a structural abnormality of the gastrointestinal (GI) tract or a disease or condition that can affect GI motility * Patient has any protocol-excluded or clinically significant medical or surgical history that could confound the study assessments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Spontaneous Bowel Movement (CSBM) Overall Responder | Change from Baseline to Week 12 | A 12-week CSBM Overall Responder was defined as a patient who for at least 9 of the 12 weeks of the treatment period had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 12-Week Spontaneous Bowl Movement (SBM) Frequency | Change from Baseline to Week 12 | The number of SBMs per week. |
| 12-week Change in Stool Consistency | Change from Baseline to Week 12 | The consistency of each BM was assessed using the 7-point Bristol Stool Form Scale: 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 7. = watery, no solid pieces \[entirely liquid\] |
| 12-week Change in Severity of Straining | Change from Baseline to Week 12 | Severity of 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. |
| 12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency | Change from Baseline to Week 12 | The number of CSBMs per week. |
| 12-week Change in Bloating | Change from Baseline to Week 12 | Bloating was based on a 5-point scale where a value of l is none and a value of 5 is very severe. |
| 12-week Change in Constipation Severity | Change from Baseline to Week 12 | Constipation severity was based on a 5-point ordinal scale where a value of l is none and a value of 5 is very severe. |
| 12-week Change in Abdominal Discomfort | Change from Baseline to Week 12 | Abdominal discomfort is based on a 5-point scale where a value of l is none and a value of 5 is very severe. |
Countries
United States
Participant flow
Recruitment details
Patient Recruitment occurred from August 2008 to August 2009 at 109 U.S. study centers.
Pre-assignment details
Patients went through a 14 to 21 day Pretreatment Period during which the patients provided qualifying bowel habit and symptoms, and rescue medicine usage information through an interactive voice response system (IVRS).
Participants by arm
| Arm | Count |
|---|---|
| Linaclotide, 145μg Linaclotide, 145μg dose, oral administration, once per day | 217 |
| Linaclotide, 290μg Linaclotide, 290μg dose, oral administration, once per day | 217 |
| Placebo Dose matched placebo, oral administration, once per day | 209 |
| Total | 643 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 10 | 8 |
| Overall Study | Lack of Efficacy | 1 | 2 | 8 |
| Overall Study | Lost to Follow-up | 4 | 10 | 3 |
| Overall Study | Other Reason | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 6 | 4 |
| Overall Study | Withdrawal by Subject | 12 | 12 | 8 |
Baseline characteristics
| Characteristic | Linaclotide, 145μg | Linaclotide, 290μg | Placebo | Total |
|---|---|---|---|---|
| Age Continuous | 47.1 years STANDARD_DEVIATION 14.2 | 47.7 years STANDARD_DEVIATION 14.2 | 49.3 years STANDARD_DEVIATION 14.3 | 48.0 years STANDARD_DEVIATION 14.3 |
| Age, Customized 18 years to 64 years | 190 Participants | 190 Participants | 181 Participants | 561 Participants |
| Age, Customized 65 years and older | 27 Participants | 27 Participants | 28 Participants | 82 Participants |
| Region of Enrollment United States | 217 participants | 217 participants | 209 participants | 643 participants |
| Sex: Female, Male Female | 191 Participants | 189 Participants | 182 Participants | 562 Participants |
| Sex: Female, Male Male | 26 Participants | 28 Participants | 27 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 217 | 30 / 217 | 14 / 209 | 20 / 177 | 1 / 95 | 2 / 90 | 0 / 86 | 1 / 90 |
| serious Total, serious adverse events | 3 / 217 | 4 / 217 | 5 / 209 | 0 / 177 | 2 / 95 | 0 / 90 | 0 / 86 | 0 / 90 |
Outcome results
Primary
Complete Spontaneous Bowel Movement (CSBM) Overall Responder
A 12-week CSBM Overall Responder was defined as a patient who for at least 9 of the 12 weeks of the treatment period had a CSBM weekly frequency rate that was 3 or greater and increased by 1 or more from baseline. 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.
Time frame: Change from Baseline to Week 12
Population: 643 randomized patients received at least 1 dose of study drug. 642 patients were included in the Intent to Treat (ITT) Population. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linaclotide, 145μg | Complete Spontaneous Bowel Movement (CSBM) Overall Responder | 46 participants |
| Linaclotide, 290μg | Complete Spontaneous Bowel Movement (CSBM) Overall Responder | 42 participants |
| Placebo | Complete Spontaneous Bowel Movement (CSBM) Overall Responder | 7 participants |
Comparison: Null hypothesis: There is no difference in the proportion of 12-week CSBM overall responders between patients taking the 145-μg dose and those taking placebo. The power, adjusted for multiplicity, was expected to be at least 90% based on study NCT00402337(MCP-103-201) data.p-value: <0.000195% CI: [3.41, 17.47]Cochran-Mantel-Haenszel
Comparison: Null hypothesis: There is no difference in the proportion of 12-week CSBM overall responders between patients taking the 290-μg dose and those taking placebo. The power, adjusted for multiplicity, was expected to be greater than 96% based on study NCT00402337(MCP-103-201) data.p-value: <0.000195% CI: [3.14, 16.59]Cochran-Mantel-Haenszel
Secondary
12-week Change in Abdominal Discomfort
Abdominal discomfort is based on a 5-point scale where a value of l is none and a value of 5 is very severe.
Time frame: Change from Baseline to Week 12
Population: 643 randomized patients received at least 1 dose of study drug. 642 patients were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 145μg | 12-week Change in Abdominal Discomfort | -0.49 units on a scale | Standard Error 0.04 |
| Linaclotide, 290μg | 12-week Change in Abdominal Discomfort | -0.44 units on a scale | Standard Error 0.04 |
| Placebo | 12-week Change in Abdominal Discomfort | -0.30 units on a scale | Standard Error 0.04 |
Secondary
12-week Change in Bloating
Bloating was based on a 5-point scale where a value of l is none and a value of 5 is very severe.
Time frame: Change from Baseline to Week 12
Population: 643 randomized patients received at least 1 dose of study drug. 642 patients were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 145μg | 12-week Change in Bloating | -0.46 units on a scale | Standard Error 0.04 |
| Linaclotide, 290μg | 12-week Change in Bloating | -0.37 units on a scale | Standard Error 0.04 |
| Placebo | 12-week Change in Bloating | -0.22 units on a scale | Standard Error 0.04 |
Secondary
12-week Change in Constipation Severity
Constipation severity was based on a 5-point ordinal scale where a value of l is none and a value of 5 is very severe.
Time frame: Change from Baseline to Week 12
Population: 643 randomized patients received at least 1 dose of study drug; 642 patients were included in the ITT Population; 10 patients who dropped out prior to finishing 1 week of the trial have missing data. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 145μg | 12-week Change in Constipation Severity | -0.90 units on a scale | Standard Error 0.05 |
| Linaclotide, 290μg | 12-week Change in Constipation Severity | -0.81 units on a scale | Standard Error 0.05 |
| Placebo | 12-week Change in Constipation Severity | -0.27 units on a scale | Standard Error 0.05 |
Secondary
12-week Change in Severity of Straining
Severity of 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.
Time frame: Change from Baseline to Week 12
Population: 643 randomized patients received at least 1 dose of study drug; 642 patients were included in the ITT Population; 101 patients with no pretreatment spontaneous bowel movements were excluded from the Straining analysis. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 145μg | 12-week Change in Severity of Straining | -1.12 units on a scale | Standard Error 0.05 |
| Linaclotide, 290μg | 12-week Change in Severity of Straining | -1.15 units on a scale | Standard Error 0.05 |
| Placebo | 12-week Change in Severity of Straining | -0.51 units on a scale | Standard Error 0.05 |
Secondary
12-week Change in Stool Consistency
The consistency of each BM was assessed using the 7-point Bristol Stool Form Scale: 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 7. = watery, no solid pieces \[entirely liquid\]
Time frame: Change from Baseline to Week 12
Population: 643 randomized patients received at least 1 dose of study drug; 642 patients were included in the ITT Population; 101 patients with no pretreatment spontaneous bowel movements were excluded from the Stool Consistency analysis. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 145μg | 12-week Change in Stool Consistency | 1.85 units on a scale | Standard Error 0.08 |
| Linaclotide, 290μg | 12-week Change in Stool Consistency | 1.84 units on a scale | Standard Error 0.08 |
| Placebo | 12-week Change in Stool Consistency | 0.58 units on a scale | Standard Error 0.09 |
Secondary
12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency
The number of CSBMs per week.
Time frame: Change from Baseline to Week 12
Population: 643 randomized patients received at least 1 dose of study drug. 642 patients were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 145μg | 12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency | 1.94 CSBMs per Week | Standard Error 0.17 |
| Linaclotide, 290μg | 12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency | 2.04 CSBMs per Week | Standard Error 0.17 |
| Placebo | 12-Week Complete Spontaneous Bowel Movement (CSBM) Frequency | 0.45 CSBMs per Week | Standard Error 0.17 |
Secondary
12-Week Spontaneous Bowl Movement (SBM) Frequency
The number of SBMs per week.
Time frame: Change from Baseline to Week 12
Population: 643 randomized patients received at least 1 dose of study drug. 642 patients were included in the ITT Population. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 145μg | 12-Week Spontaneous Bowl Movement (SBM) Frequency | 3.03 SBMs per Week | Standard Error 0.21 |
| Linaclotide, 290μg | 12-Week Spontaneous Bowl Movement (SBM) Frequency | 2.98 SBMs per Week | Standard Error 0.21 |
| Placebo | 12-Week Spontaneous Bowl Movement (SBM) Frequency | 1.08 SBMs per Week | Standard Error 0.22 |