Irritable Bowel Syndrome With Constipation
Conditions
Keywords
Irritable Bowel Syndrome with Constipation, IBS, Irritable Bowel Syndrome, linaclotide acetate, linaclotide, MD-1100
Brief summary
The purpose of this study is to determine the safety, efficacy, and dose response of a range of oral doses of linaclotide administered to patients meeting criteria for IBS-C.
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
* Must not be pregnant or breastfeeding and agree to use birth control; * Completion of a negative colonoscopy as per American Gastroenterology Association (AGA) criteria and no clinically-significant laboratory or physical examination findings; * Meets protocol-defined criteria for IBS-C, including stool frequency, straining, stool consistency, abdominal pain, and abdominal discomfort criteria; * Demonstrates English fluency and has access to a touch-tone telephone.
Exclusion criteria
* Recent history of mushy or watery stools; * Various medical conditions, medical histories, or family medical histories that would not make the patient a good candidate for the study; * Clinically-significant alarm symptoms; * Secondary causes of constipation or evacuation disorders; * Surgery to the gastrointestinal tract; * Usage of prohibited medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Weekly Normalized Complete Spontaneous Bowel Movement (CSBM) Rate During Weeks 1 Through 12 of the Treatment Period | Change from Baseline to Week 12 | The change in the weekly normalized CSBM Rate during Weeks 1 through 12 of the Treatment Period from the weekly normalized CSBM Rate obtained during the Pretreatment Period. The CSBM rate was normalized based on the number of CSBMs occurring in that week, adjusting for differences in the duration of the week and black-out periods (time not covered due to a missed IVRS call) versus 7x24 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Weekly Normalized SBM Rate for the Treatment Period | Change from Baseline to Week 12 | SBMs were measured daily during the treatment period by patient calls to the IVRS. |
| Change From Baseline in Stool Consistency (7-point Ordinal BSFS) for the Treatment Period | Change from Baseline to Week 12 | Stool consistency analyses were performed using the 7-point Bristol Stool Form Scale (BSFS), whereby a score of 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; and 7 = watery, no solid pieces (entirely liquid). |
| CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | Change from Baseline to Week 12 | For each week of the Treatment and Posttreatment 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 the baseline weekly CSBM rate. |
| Change From Baseline in Degree of Relief of Irritable Bowel Syndrome (IBS) Symptoms (7-point Balanced Scale) for the Treatment Period | Change from Baseline to Week 12 | Patients provided a weekly assessment of Degree of Relief of IBS Symptoms using a 7-point balanced scale (1=completely relieved, 2=considerably relieved, 3=somewhat relieved, 4=unchanged, 5=somewhat worse, 6=considerably worse, 7=as bad as I can imagine). |
| Change From Baseline in Abdominal Pain (5-point Ordinal Scale) for the Treatment Period | Change from Baseline to Week 12 | During the study, patients provided their self assessment of abdominal pain using a 5-point ordinal scale (1=none, 2=mild, 3=moderate, 4=severe, 5=very severe |
| Change From Baseline in Straining (5-point Ordinal Scale) for the Treatment Period | Change from Baseline to Week 12 | 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
Canada, United States
Participant flow
Recruitment details
Patient recruitment occurred over a 12 month period from March 2007 to February 2008 at 92 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 |
|---|---|
| 72 µg Linaclotide Acetate Linaclotide, 72μg dose, oral administration, once per day | 79 |
| 145 µg Linaclotide Acetate Linaclotide, 145μg dose, oral administration, once per day | 82 |
| 290 µg Linaclotide Acetate Linaclotide, 290μg dose, oral administration, once per day | 85 |
| 579 µg Linaclotide Acetate Linaclotide, 579μg dose, oral administration, once per day | 89 |
| Matching Placebo Dose-matched placebo, oral administration, once per day | 85 |
| Total | 420 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 | 3 | 10 | 2 |
| Overall Study | Lost to Follow-up | 3 | 2 | 5 | 3 | 6 |
| Overall Study | Noncompliance | 1 | 0 | 0 | 2 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 7 | 6 | 3 | 11 |
Baseline characteristics
| Characteristic | 72 µg Linaclotide Acetate | 145 µg Linaclotide Acetate | 290 µg Linaclotide Acetate | 579 µg Linaclotide Acetate | Matching Placebo | Total |
|---|---|---|---|---|---|---|
| Age Continuous | 42.3 years STANDARD_DEVIATION 12.5 | 45.6 years STANDARD_DEVIATION 10.8 | 45.8 years STANDARD_DEVIATION 11.4 | 43.7 years STANDARD_DEVIATION 11.4 | 44.3 years STANDARD_DEVIATION 11.3 | 44.4 years STANDARD_DEVIATION 11.5 |
| Age, Customized 18 years to 65 years | 77 Participants | 79 Participants | 81 Participants | 86 Participants | 85 Participants | 408 Participants |
| Age, Customized Older than 65 years | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 0 Participants | 12 Participants |
| Region of Enrollment Canada | 4 participants | 3 participants | 5 participants | 3 participants | 4 participants | 19 participants |
| Region of Enrollment United States | 75 participants | 79 participants | 80 participants | 86 participants | 81 participants | 401 participants |
| Sex: Female, Male Female | 74 Participants | 78 Participants | 78 Participants | 79 Participants | 78 Participants | 387 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 7 Participants | 10 Participants | 7 Participants | 33 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 | 21 / 79 | 23 / 82 | 26 / 85 | 30 / 89 | 17 / 85 |
| serious Total, serious adverse events | 0 / 79 | 0 / 82 | 1 / 85 | 0 / 89 | 0 / 85 |
Outcome results
Primary
Change From Baseline in the Weekly Normalized Complete Spontaneous Bowel Movement (CSBM) Rate During Weeks 1 Through 12 of the Treatment Period
The change in the weekly normalized CSBM Rate during Weeks 1 through 12 of the Treatment Period from the weekly normalized CSBM Rate obtained during the Pretreatment Period. The CSBM rate was normalized based on the number of CSBMs occurring in that week, adjusting for differences in the duration of the week and black-out periods (time not covered due to a missed IVRS call) versus 7x24 hours.
Time frame: Change from Baseline to Week 12
Population: The Intent-to-treat (ITT) Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 72 ug Linaclotide Acetate | Change From Baseline in the Weekly Normalized Complete Spontaneous Bowel Movement (CSBM) Rate During Weeks 1 Through 12 of the Treatment Period | 2.90 CSBMs per week | Standard Error 0.385 |
| 145 ug Linaclotide Acetate | Change From Baseline in the Weekly Normalized Complete Spontaneous Bowel Movement (CSBM) Rate During Weeks 1 Through 12 of the Treatment Period | 2.49 CSBMs per week | Standard Error 0.38 |
| 290 ug Linaclotide Acetate | Change From Baseline in the Weekly Normalized Complete Spontaneous Bowel Movement (CSBM) Rate During Weeks 1 Through 12 of the Treatment Period | 3.61 CSBMs per week | Standard Error 0.372 |
| 579 ug Linaclotide Acetate | Change From Baseline in the Weekly Normalized Complete Spontaneous Bowel Movement (CSBM) Rate During Weeks 1 Through 12 of the Treatment Period | 2.68 CSBMs per week | Standard Error 0.369 |
| Matching Placebo | Change From Baseline in the Weekly Normalized Complete Spontaneous Bowel Movement (CSBM) Rate During Weeks 1 Through 12 of the Treatment Period | 1.01 CSBMs per week | Standard Error 0.372 |
Comparison: For each of the 4 active linaclotide groups, the null hypothesis was that there was no difference between placebo and the dose group in the change from baseline in the weekly normalized CSBM Rate. An observed cases (OC) approach to missing post-baseline data was applied: any missing data were not imputed.p-value: 0.0002ANCOVA
Comparison: For each of the 4 active linaclotide groups, the null hypothesis was that there was no difference between placebo and the dose group in the change from baseline in the weekly normalized CSBM Rate. An observed cases (OC) approach to missing post-baseline data was applied: any missing data were not imputed.p-value: 0.0036ANCOVA
Comparison: For each of the 4 active linaclotide groups, the null hypothesis was that there was no difference between placebo and the dose group in the change from baseline in the weekly normalized CSBM Rate. An observed cases (OC) approach to missing post-baseline data was applied: any missing data were not imputed.p-value: <0.0001ANCOVA
Comparison: For each of the 4 active linaclotide groups, the null hypothesis was that there was no difference between placebo and the dose group in the change from baseline in the weekly normalized CSBM Rate. An observed cases (OC) approach to missing post-baseline data was applied: any missing data were not imputed.p-value: 0.0008ANCOVA
Secondary
Change From Baseline in Abdominal Pain (5-point Ordinal Scale) for the Treatment Period
During the study, patients provided their self assessment of abdominal pain using a 5-point ordinal scale (1=none, 2=mild, 3=moderate, 4=severe, 5=very severe
Time frame: Change from Baseline to Week 12
Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 72 ug Linaclotide Acetate | Change From Baseline in Abdominal Pain (5-point Ordinal Scale) for the Treatment Period | -0.71 units on a scale | Standard Error 0.075 |
| 145 ug Linaclotide Acetate | Change From Baseline in Abdominal Pain (5-point Ordinal Scale) for the Treatment Period | -0.71 units on a scale | Standard Error 0.074 |
| 290 ug Linaclotide Acetate | Change From Baseline in Abdominal Pain (5-point Ordinal Scale) for the Treatment Period | -0.90 units on a scale | Standard Error 0.073 |
| 579 ug Linaclotide Acetate | Change From Baseline in Abdominal Pain (5-point Ordinal Scale) for the Treatment Period | -0.86 units on a scale | Standard Error 0.072 |
| Matching Placebo | Change From Baseline in Abdominal Pain (5-point Ordinal Scale) for the Treatment Period | -0.49 units on a scale | Standard Error 0.073 |
Secondary
Change From Baseline in Degree of Relief of Irritable Bowel Syndrome (IBS) Symptoms (7-point Balanced Scale) for the Treatment Period
Patients provided a weekly assessment of Degree of Relief of IBS Symptoms using a 7-point balanced scale (1=completely relieved, 2=considerably relieved, 3=somewhat relieved, 4=unchanged, 5=somewhat worse, 6=considerably worse, 7=as bad as I can imagine).
Time frame: Change from Baseline to Week 12
Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency). 13 patients who dropped out prior to finishing 1 week of the trial have missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 72 ug Linaclotide Acetate | Change From Baseline in Degree of Relief of Irritable Bowel Syndrome (IBS) Symptoms (7-point Balanced Scale) for the Treatment Period | -1.33 units on a scale | Standard Error 0.108 |
| 145 ug Linaclotide Acetate | Change From Baseline in Degree of Relief of Irritable Bowel Syndrome (IBS) Symptoms (7-point Balanced Scale) for the Treatment Period | -1.37 units on a scale | Standard Error 0.107 |
| 290 ug Linaclotide Acetate | Change From Baseline in Degree of Relief of Irritable Bowel Syndrome (IBS) Symptoms (7-point Balanced Scale) for the Treatment Period | -1.66 units on a scale | Standard Error 0.105 |
| 579 ug Linaclotide Acetate | Change From Baseline in Degree of Relief of Irritable Bowel Syndrome (IBS) Symptoms (7-point Balanced Scale) for the Treatment Period | -1.49 units on a scale | Standard Error 0.104 |
| Matching Placebo | Change From Baseline in Degree of Relief of Irritable Bowel Syndrome (IBS) Symptoms (7-point Balanced Scale) for the Treatment Period | -0.81 units on a scale | Standard Error 0.105 |
Secondary
Change From Baseline in Stool Consistency (7-point Ordinal BSFS) for the Treatment Period
Stool consistency analyses were performed using the 7-point Bristol Stool Form Scale (BSFS), whereby a score of 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; and 7 = watery, no solid pieces (entirely liquid).
Time frame: Change from Baseline to Week 12
Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency). 15 patients with no pretreatment spontaneous bowel movements were excluded from the Stool Consistency analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 72 ug Linaclotide Acetate | Change From Baseline in Stool Consistency (7-point Ordinal BSFS) for the Treatment Period | 1.91 units on a scale | Standard Error 0.133 |
| 145 ug Linaclotide Acetate | Change From Baseline in Stool Consistency (7-point Ordinal BSFS) for the Treatment Period | 1.80 units on a scale | Standard Error 0.131 |
| 290 ug Linaclotide Acetate | Change From Baseline in Stool Consistency (7-point Ordinal BSFS) for the Treatment Period | 2.28 units on a scale | Standard Error 0.127 |
| 579 ug Linaclotide Acetate | Change From Baseline in Stool Consistency (7-point Ordinal BSFS) for the Treatment Period | 2.20 units on a scale | Standard Error 0.127 |
| Matching Placebo | Change From Baseline in Stool Consistency (7-point Ordinal BSFS) for the Treatment Period | 0.56 units on a scale | Standard Error 0.127 |
Secondary
Change From Baseline in Straining (5-point Ordinal Scale) 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 12
Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency). 15 patients with no pretreatment spontaneous bowel movements were excluded from the Straining analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 72 ug Linaclotide Acetate | Change From Baseline in Straining (5-point Ordinal Scale) for the Treatment Period | -1.23 units on a scale | Standard Error 0.081 |
| 145 ug Linaclotide Acetate | Change From Baseline in Straining (5-point Ordinal Scale) for the Treatment Period | -1.20 units on a scale | Standard Error 0.08 |
| 290 ug Linaclotide Acetate | Change From Baseline in Straining (5-point Ordinal Scale) for the Treatment Period | -1.48 units on a scale | Standard Error 0.077 |
| 579 ug Linaclotide Acetate | Change From Baseline in Straining (5-point Ordinal Scale) for the Treatment Period | -1.35 units on a scale | Standard Error 0.078 |
| Matching Placebo | Change From Baseline in Straining (5-point Ordinal Scale) for the Treatment Period | -0.71 units on a scale | Standard Error 0.078 |
Secondary
Change From Baseline in the Weekly Normalized SBM Rate for the Treatment Period
SBMs were measured daily during the treatment period by patient calls to the IVRS.
Time frame: Change from Baseline to Week 12
Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 72 ug Linaclotide Acetate | Change From Baseline in the Weekly Normalized SBM Rate for the Treatment Period | 4.62 SBMs per week | Standard Error 0.457 |
| 145 ug Linaclotide Acetate | Change From Baseline in the Weekly Normalized SBM Rate for the Treatment Period | 4.36 SBMs per week | Standard Error 0.453 |
| 290 ug Linaclotide Acetate | Change From Baseline in the Weekly Normalized SBM Rate for the Treatment Period | 4.97 SBMs per week | Standard Error 0.442 |
| 579 ug Linaclotide Acetate | Change From Baseline in the Weekly Normalized SBM Rate for the Treatment Period | 5.64 SBMs per week | Standard Error 0.439 |
| Matching Placebo | Change From Baseline in the Weekly Normalized SBM Rate for the Treatment Period | 1.68 SBMs per week | Standard Error 0.442 |
Secondary
CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate)
For each week of the Treatment and Posttreatment 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 the baseline weekly CSBM rate.
Time frame: Change from Baseline to Week 12
Population: The ITT Population included 419 patients of the Safety Population who also had ≥ 1 post-dose evaluation of the primary efficacy assessment (i.e., CSBM Frequency).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 72 ug Linaclotide Acetate | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 20 participants |
| 145 ug Linaclotide Acetate | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 16 participants |
| 290 ug Linaclotide Acetate | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 27 participants |
| 579 ug Linaclotide Acetate | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 21 participants |
| Matching Placebo | CSBM 75% Responder for the Treatment Period (Based on the Normalized Rate) | 10 participants |