Chronic Constipation
Conditions
Keywords
Constipation, Chronic Constipation, Microbia, linaclotide, linaclotide acetate, MD-1100
Brief summary
The primary purpose of this study is to evaluate the efficacy and safety of administration of linaclotide acetate in patients with chronic constipation.
Interventions
oral, once daily.
DRUGMatching placebo
oral, once daily
Sponsors
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 is 18 years of age or older * Patient meets colonoscopy requirements according to the American Gastroenterological Association * Patient meets criteria for chronic constipation including weekly bowel movement frequency requirements and reports one or more symptoms of constipation according to protocol requirements * Patient has successfully completed study requirements with no clinically-significant findings: physical exam, ECG, clinical laboratory tests * Patient is fluent in English
Exclusion criteria
* Patient reports loose or watery stools * Patient meets criteria for IBS including protocol-defined abdominal discomfort or pain * Patient may not take prohibited medications per protocol * Medical diagnoses, medical conditions, or family history that would not make the patient a good candidate for the study or limit the patient's ability to complete the clinical study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Pretreatment in Weekly Normalized Spontaneous Bowel Movement (SBM) Frequency | Change from Baseline to Week 4 | Change in SBM frequency during Weeks 1 through 4 of the treatment period from the weekly SBM rate obtained during the pretreatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | Change from Baseline to Week 4 | A patient was an SBM 75% Responder if the patient was an SBM Responder for ≥3 of the 4 treatment period weeks. For each week of the treatment and postreatment periods, a patient was considered an SBM Responder if for that week the patient 1) completed ≥4 days of IVRS questions,2) had an SBM rate of ≥ 3 for the week, and 3) had an increase in SBM rate of ≥ 1 from their baseline weekly SBM rate. |
| CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | Change from Baseline to Week 4 | A patient was a complete spontaneous bowel movement (CSBM) 75% Responder if the patient was a CSBM Responder for ≥3 of the 4 treatment period weeks. For each week of the treatment and postreatment periods, a patient was considered a CSBM Responder if for that week the patient 1) completed ≥4 days of IVRS questions,2) had a CSBM rate of ≥ 3 for the week, and 3) had an increase in CSBM rate of ≥ 1 from their baseline weekly CSBM rate. |
| Change From Baseline in the Weekly Normalized CSBM Rate for the Treatment Period | Change from Baseline to Week 4 | CSBMs measured daily during the treatment period. During each daily phone call into the IVRS, patients were asked: How many bowel movements did you have today or yesterday after your last call? |
| Change From Baseline in Stool Consistency (BSFS) Score for the Treatment Period | Change from Baseline to Week 4 | Stool consistency analyses were performed using the 7-point BSFS, whereby a score of 1 = 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 = entirely liquid. |
| Change From Baseline in Straining Score for the Treatment Period | Change from Baseline to Week 4 | Straining was assessed using a 5-point ordinal scale, whereby a score of 1 = not at all, 2 = a little bit, 3 = a moderate amount, 4 = a great deal, and 5 = an extreme amount. |
Countries
United States
Participant flow
Recruitment details
Patient recruitment occurred over a 13 month period from November 2006 to December 2007 at 57 US study sites.
Pre-assignment details
Patients went through a 14 to 17 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, 72μg Linaclotide, 72μg dose, oral administration, once per day | 59 |
| Linaclotide, 145μg Linaclotide, 145μg dose, oral administration, once per day. One patient was randomized into the study but did not receive ≥ 1 dose of study drug, thus was not included in the Safety Population. | 56 |
| Linaclotide, 290μg Linaclotide, 290μg dose, oral administration, once per day | 62 |
| Linaclotide, 579μg Linaclotide, 579μg dose, oral administration, once per day | 63 |
| Placebo Dose-matched placebo, oral administration, once per day. | 69 |
| Total | 309 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 2 | 3 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 2 | 0 |
| Overall Study | Noncompliance | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Other Reason | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 3 | 1 | 6 | 4 |
Baseline characteristics
| Characteristic | Linaclotide, 72μg | Linaclotide, 145μg | Linaclotide, 290μg | Linaclotide, 579μg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age Continuous | 45.9 years STANDARD_DEVIATION 14.1 | 46.4 years STANDARD_DEVIATION 11.7 | 48.4 years STANDARD_DEVIATION 12.7 | 49.2 years STANDARD_DEVIATION 14 | 46.1 years STANDARD_DEVIATION 15.5 | 47.2 years STANDARD_DEVIATION 13.7 |
| Age, Customized 18 years to 65 years | 52 Participants | 53 Participants | 57 Participants | 57 Participants | 64 Participants | 283 Participants |
| Age, Customized Older than 65 years | 7 Participants | 3 Participants | 5 Participants | 6 Participants | 5 Participants | 26 Participants |
| Region of Enrollment United States | 59 participants | 56 participants | 62 participants | 63 participants | 69 participants | 309 participants |
| Sex: Female, Male Female | 55 Participants | 54 Participants | 58 Participants | 56 Participants | 61 Participants | 284 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 4 Participants | 7 Participants | 8 Participants | 25 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 59 | 11 / 56 | 5 / 62 | 11 / 63 | 7 / 69 |
| serious Total, serious adverse events | 0 / 59 | 0 / 56 | 0 / 62 | 0 / 63 | 2 / 69 |
Outcome results
Primary
Change From Pretreatment in Weekly Normalized Spontaneous Bowel Movement (SBM) Frequency
Change in SBM frequency during Weeks 1 through 4 of the treatment period from the weekly SBM rate obtained during the pretreatment period.
Time frame: Change from Baseline to Week 4
Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 How many bowel movements did you have today or yesterday since your last call? were included in the intent-to-treat (ITT) Population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 72μg | Change From Pretreatment in Weekly Normalized Spontaneous Bowel Movement (SBM) Frequency | 2.59 SBMs per week | Standard Error 0.407 |
| Linaclotide, 145μg | Change From Pretreatment in Weekly Normalized Spontaneous Bowel Movement (SBM) Frequency | 3.25 SBMs per week | Standard Error 0.412 |
| Linaclotide, 290μg | Change From Pretreatment in Weekly Normalized Spontaneous Bowel Movement (SBM) Frequency | 3.57 SBMs per week | Standard Error 0.391 |
| Linaclotide, 579μg | Change From Pretreatment in Weekly Normalized Spontaneous Bowel Movement (SBM) Frequency | 4.29 SBMs per week | Standard Error 0.394 |
| Placebo | Change From Pretreatment in Weekly Normalized Spontaneous Bowel Movement (SBM) Frequency | 1.45 SBMs per week | Standard Error 0.383 |
Comparison: The null hypothesis is that the active treatment group is equal to the placebo group.p-value: 0.0337ANCOVA
Comparison: The null hypothesis is that the active treatment group is equal to the placebo group.p-value: 0.001ANCOVA
Comparison: The null hypothesis is that the active treatment group is equal to the placebo group.p-value: <0.0001ANCOVA
Comparison: The null hypothesis is that the active treatment group is equal to the placebo group.p-value: <0.0001ANCOVA
Secondary
Change From Baseline in Stool Consistency (BSFS) Score for the Treatment Period
Stool consistency analyses were performed using the 7-point BSFS, whereby a score of 1 = 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 = entirely liquid.
Time frame: Change from Baseline to Week 4
Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 How many bowel movements did you have today or yesterday since your last call? were included in the ITT. 29 patients with no pretreatment spontaneous bowel movements were excluded from the Stool Consistency analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 72μg | Change From Baseline in Stool Consistency (BSFS) Score for the Treatment Period | 1.35 units on a scale | Standard Error 0.182 |
| Linaclotide, 145μg | Change From Baseline in Stool Consistency (BSFS) Score for the Treatment Period | 1.57 units on a scale | Standard Error 0.177 |
| Linaclotide, 290μg | Change From Baseline in Stool Consistency (BSFS) Score for the Treatment Period | 1.68 units on a scale | Standard Error 0.175 |
| Linaclotide, 579μg | Change From Baseline in Stool Consistency (BSFS) Score for the Treatment Period | 2.00 units on a scale | Standard Error 0.171 |
| Placebo | Change From Baseline in Stool Consistency (BSFS) Score for the Treatment Period | 0.50 units on a scale | Standard Error 0.17 |
Secondary
Change From Baseline in Straining Score for the Treatment Period
Straining was assessed using a 5-point ordinal scale, whereby a score of 1 = not at all, 2 = a little bit, 3 = a moderate amount, 4 = a great deal, and 5 = an extreme amount.
Time frame: Change from Baseline to Week 4
Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 How many bowel movements did you have today or yesterday since your last call? were included in the ITT Population. 29 patients with no pretreatment spontaneous bowel movements were excluded from the Straining analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 72μg | Change From Baseline in Straining Score for the Treatment Period | -0.71 units on a scale | Standard Error 0.102 |
| Linaclotide, 145μg | Change From Baseline in Straining Score for the Treatment Period | -0.97 units on a scale | Standard Error 0.098 |
| Linaclotide, 290μg | Change From Baseline in Straining Score for the Treatment Period | -1.11 units on a scale | Standard Error 0.097 |
| Linaclotide, 579μg | Change From Baseline in Straining Score for the Treatment Period | -1.14 units on a scale | Standard Error 0.095 |
| Placebo | Change From Baseline in Straining Score for the Treatment Period | -0.52 units on a scale | Standard Error 0.094 |
Secondary
Change From Baseline in the Weekly Normalized CSBM Rate for the Treatment Period
CSBMs measured daily during the treatment period. During each daily phone call into the IVRS, patients were asked: How many bowel movements did you have today or yesterday after your last call?
Time frame: Change from Baseline to Week 4
Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 How many bowel movements did you have today or yesterday since your last call? were included in the ITT Population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linaclotide, 72μg | Change From Baseline in the Weekly Normalized CSBM Rate for the Treatment Period | 1.47 CSBMs per week | Standard Error 0.295 |
| Linaclotide, 145μg | Change From Baseline in the Weekly Normalized CSBM Rate for the Treatment Period | 1.59 CSBMs per week | Standard Error 0.298 |
| Linaclotide, 290μg | Change From Baseline in the Weekly Normalized CSBM Rate for the Treatment Period | 1.75 CSBMs per week | Standard Error 0.283 |
| Linaclotide, 579μg | Change From Baseline in the Weekly Normalized CSBM Rate for the Treatment Period | 2.26 CSBMs per week | Standard Error 0.285 |
| Placebo | Change From Baseline in the Weekly Normalized CSBM Rate for the Treatment Period | 0.45 CSBMs per week | Standard Error 0.279 |
Secondary
CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate)
A patient was a complete spontaneous bowel movement (CSBM) 75% Responder if the patient was a CSBM Responder for ≥3 of the 4 treatment period weeks. For each week of the treatment and postreatment periods, a patient was considered a CSBM Responder if for that week the patient 1) completed ≥4 days of IVRS questions,2) had a CSBM rate of ≥ 3 for the week, and 3) had an increase in CSBM rate of ≥ 1 from their baseline weekly CSBM rate.
Time frame: Change from Baseline to Week 4
Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 How many bowel movements did you have today or yesterday since your last call? were included in the ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linaclotide, 72μg | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 11 participants |
| Linaclotide, 145μg | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 15 participants |
| Linaclotide, 290μg | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 20 participants |
| Linaclotide, 579μg | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 18 participants |
| Placebo | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 5 participants |
Secondary
SBM 75% Responder for the Treatment Period (Based on the Normalized Rate)
A patient was an SBM 75% Responder if the patient was an SBM Responder for ≥3 of the 4 treatment period weeks. For each week of the treatment and postreatment periods, a patient was considered an SBM Responder if for that week the patient 1) completed ≥4 days of IVRS questions,2) had an SBM rate of ≥ 3 for the week, and 3) had an increase in SBM rate of ≥ 1 from their baseline weekly SBM rate.
Time frame: Change from Baseline to Week 4
Population: 307 patients who received ≥ 1 capsule of study drug and had ≥ 1 post-baseline response to the IVRS Treatment Period Question #12 How many bowel movements did you have today or yesterday since your last call? were included in the ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linaclotide, 72μg | SBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 35 participants |
| Linaclotide, 145μg | SBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 31 participants |
| Linaclotide, 290μg | SBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 38 participants |
| Linaclotide, 579μg | SBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 42 participants |
| Placebo | SBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 22 participants |