Chronic Constipation
Conditions
Keywords
Constipation, Chronic Constipation, Linaclotide
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 treatment group that meet the protocol definition for Complete Spontaneous Bowel Movement (CSBM) Overall Responder
Interventions
Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study
Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study
DRUGPlacebo
Oral, once daily each morning at least 30 minutes before breakfast for the duration of the study
Sponsors
Ironwood Pharmaceuticals, Inc.
Forest Laboratories
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 responders 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 Bowel Movement (SBM) Frequency Rate | Change from Baseline to Week 12 | A patient's 12-week spontaneous bowel movement (SBM) frequency rate was the number of SBMs per week calculated over the 12-weeks of the treatment period. |
| 12-Week 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 Severity of Straining | Change from Baseline to Week 12 | 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 Rate | Change from Baseline to Week 12 | The number of CSBMs per week. |
| 12-Week 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 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 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
Canada, United States
Participant flow
Recruitment details
Patient Recruitment occurred from October 2008 to March 2009 at 103 study centers (95 in the United States and 8 in Canada).
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 |
|---|---|
| Placebo Dose matched placebo, oral administration, once per day. | 215 |
| Linaclotide 145µg Linaclotide, 145µg dose, oral administration, once per day | 213 |
| Linaclotide 290µg Linaclotide, 290µg dose, oral administration, once per day | 205 |
| Total | 633 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 21 | 20 |
| Overall Study | Lack of Efficacy | 4 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 9 | 6 |
| Overall Study | Other Reason | 3 | 1 | 2 |
| Overall Study | Protocol Violation | 4 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 6 | 6 |
Baseline characteristics
| Characteristic | Placebo | Linaclotide 145µg | Linaclotide 290µg | Total |
|---|---|---|---|---|
| Age Continuous | 47.0 years STANDARD_DEVIATION 13.5 | 48.5 years STANDARD_DEVIATION 12.3 | 47.3 years STANDARD_DEVIATION 13.3 | 47.6 years STANDARD_DEVIATION 13 |
| Age, Customized 18 years to 64 years | 188 participants | 189 participants | 183 participants | 560 participants |
| Age, Customized 65 years and older | 27 participants | 24 participants | 22 participants | 73 participants |
| Region of Enrollment Canada | 7 participants | 5 participants | 7 participants | 19 participants |
| Region of Enrollment United States | 208 participants | 208 participants | 198 participants | 614 participants |
| Sex: Female, Male Female | 196 Participants | 195 Participants | 181 Participants | 572 Participants |
| Sex: Female, Male Male | 19 Participants | 18 Participants | 24 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 35 / 215 | 70 / 213 | 49 / 205 |
| serious Total, serious adverse events | 4 / 215 | 3 / 213 | 7 / 205 |
Outcome results
Primary
Complete Spontaneous Bowel Movement (CSBM) Overall Responder
A 12-week CSBM overall responders 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: A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the Intent to Treat (ITT) Population. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Complete Spontaneous Bowel Movement (CSBM) Overall Responder | Responder | 13 participants |
| Placebo | Complete Spontaneous Bowel Movement (CSBM) Overall Responder | Nonresponder | 202 participants |
| Linaclotide 145µg | Complete Spontaneous Bowel Movement (CSBM) Overall Responder | Responder | 34 participants |
| Linaclotide 145µg | Complete Spontaneous Bowel Movement (CSBM) Overall Responder | Nonresponder | 179 participants |
| Linaclotide 290µg | Complete Spontaneous Bowel Movement (CSBM) Overall Responder | Responder | 43 participants |
| Linaclotide 290µg | Complete Spontaneous Bowel Movement (CSBM) Overall Responder | Nonresponder | 159 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 90% based on study NCT00402337 (MCP-103-201) data.p-value: 0.001295% CI: [1.5, 5.72]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 96% based on study NCT00460811 (MCP-103-202) data.p-value: <0.000195% CI: [2.2, 8.1]Cochran-Mantel-Haenszel
Secondary
12-Week 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: A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the Intent to Treat (ITT) Population. 1 additional patient without a baseline Abdominal Discomfort score was excluded from analysis in this endpoint. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 12-Week Abdominal Discomfort | -0.271 units on a scale | Standard Error 0.043 |
| Linaclotide 145µg | 12-Week Abdominal Discomfort | -0.455 units on a scale | Standard Error 0.044 |
| Linaclotide 290µg | 12-Week Abdominal Discomfort | -0.485 units on a scale | Standard Error 0.045 |
Secondary
12-Week 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: A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the ITT population; 1 additional patient without a baseline Bloating score was excluded from analysis in this endpoint. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 12-Week Bloating | -0.244 units on a scale | Standard Error 0.048 |
| Linaclotide 145µg | 12-Week Bloating | -0.432 units on a scale | Standard Error 0.049 |
| Linaclotide 290µg | 12-Week Bloating | -0.485 units on a scale | Standard Error 0.049 |
Secondary
12-week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate
The number of CSBMs per week.
Time frame: Change from Baseline to Week 12
Population: A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the Intent to Treat (ITT) Population. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 12-week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate | 0.614 CSBM per week | Standard Error 0.209 |
| Linaclotide 145µg | 12-week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate | 2.011 CSBM per week | Standard Error 0.215 |
| Linaclotide 290µg | 12-week Complete Spontaneous Bowel Movement (CSBM) Frequency Rate | 2.653 CSBM per week | Standard Error 0.217 |
Secondary
12-Week 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: A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the ITT population; 11 additional patients who dropped out prior to finishing 1 week of the trial were excluded from the Constipation Severity endpoint. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 12-Week Constipation Severity | -0.306 units on a scale | Standard Error 0.062 |
| Linaclotide 145µg | 12-Week Constipation Severity | -0.908 units on a scale | Standard Error 0.063 |
| Linaclotide 290µg | 12-Week Constipation Severity | -0.954 units on a scale | Standard Error 0.064 |
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.
Time frame: Change from Baseline to Week 12
Population: A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the ITT Population; 97 Patients with no pretreatment spontaneous bowel movements were excluded from the 12-Week Severity of Straining analysis. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 12-Week Severity of Straining | -0.554 units on a scale | Standard Error 0.06 |
| Linaclotide 145µg | 12-Week Severity of Straining | -1.141 units on a scale | Standard Error 0.061 |
| Linaclotide 290µg | 12-Week Severity of Straining | -1.208 units on a scale | Standard Error 0.063 |
Secondary
12-Week Spontaneous Bowel Movement (SBM) Frequency Rate
A patient's 12-week spontaneous bowel movement (SBM) frequency rate was the number of SBMs per week calculated over the 12-weeks of the treatment period.
Time frame: Change from Baseline to Week 12
Population: A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the Intent to Treat (ITT) Population. An observed-cases approach to missing postbaseline data was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 12-Week Spontaneous Bowel Movement (SBM) Frequency Rate | 1.113 SBM per week | Standard Error 0.265 |
| Linaclotide 145µg | 12-Week Spontaneous Bowel Movement (SBM) Frequency Rate | 3.466 SBM per week | Standard Error 0.272 |
| Linaclotide 290µg | 12-Week Spontaneous Bowel Movement (SBM) Frequency Rate | 3.675 SBM per week | Standard Error 0.275 |
Secondary
12-Week 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: A total of 633 patients were randomized to treatment and received at least 1 dose of study drug. 630 patients were included in the ITT Population; 97 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 12-Week Stool Consistency | 0.572 units on a scale | Standard Error 0.098 |
| Linaclotide 145µg | 12-Week Stool Consistency | 1.823 units on a scale | Standard Error 0.1 |
| Linaclotide 290µg | 12-Week Stool Consistency | 2.009 units on a scale | Standard Error 0.103 |