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| Name | Class |
|---|---|
| Ironwood Pharmaceuticals, Inc. | INDUSTRY |
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The purpose of this study was to evaluate the safety and efficacy of linaclotide for the treatment of opioid-induced constipation (OIC), in adults receiving stable opioid treatment for chronic non-cancer pain that has been present for a minimum of 3 months.
This study included up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Patients meeting the entry criteria were randomized to 1 of 2 doses of linaclotide or placebo once per day for 8 weeks. This 8-week study assessed the effects of linaclotide on bowel movement frequency, as well as other bowel symptoms of OIC.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Linaclotide 145 micrograms | Experimental | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. |
|
| Linaclotide 290 micrograms | Experimental | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. |
|
| Placebo | Experimental | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Linaclotide 145 micrograms | Drug |
|
| |
| Linaclotide 290 micrograms |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week) | Change from baseline in 8-Week SBM frequency rate (SBMs/week) during the Treatment Period. | Baseline (Week 0) to Week 8 |
| Measure | Description | Time Frame |
|---|---|---|
| Time to First SBM After the First Dose of Investigational Product | The median time to the first SBM after the first dose of investigational product | Baseline (Day 0) up to 8 weeks |
| Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria |
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Inclusion Criteria:
Patient has chronic non-cancer pain that has been present for a minimum of 3 months
Patient has been receiving a stable oral dose of a full-opioid agonist for at least 4 days per week during the 8 consecutive weeks
Patient meets protocol criteria for Opioid-Induced Constipation (OIC): < 3 spontaneous bowel movements (SBMs) per week and reports one of the following symptoms for at least 4 weeks:
Patient meets the colonoscopy requirements defined by the American Gastroenterological Association guidelines
Patient has successfully completed protocol procedures (with no clinically significant findings)
Patient is compliant with Interactive Voice Response System (IVRS) for daily diary reporting
Patient has a total of < 6 SBMs in IVRS during the 14 days before and up to the time of Randomization
Patient has adequate relief and well-controlled pain with current dose of opioid
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Patricia D'Astoli, RN | Forest Laboratories, LLC, an Allergan Affiliate | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Forest Investigative Site 002 | Anniston | Alabama | 36207 | United States | ||
| Forest Investigative Site 001 |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32310620 | Derived | Brenner DM, Argoff CE, Fox SM, Bochenek W, D'Astoli P, Blakesley RE, Reasner DS, O'Dea CR, Cash BD. Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study. Pain. 2020 May;161(5):1027-1036. doi: 10.1097/j.pain.0000000000001754. |
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14 calendar days (minimum) to 21 calendar days (maximum) before randomization, participants had to provide information about bowel habits, symptom severity, and rescue medication use through daily IVRS calls. A total of 254 patients were randomized to treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. |
| FG001 | Linaclotide 145 Micrograms |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Drug |
|
|
| Placebo | Drug | Matching placebo |
|
A 6/8 Week SBM 3 + 1 responder was a participant who met the weekly SBM 3 + 1 responder criteria for at least 6 out of the 8 weeks of the Treatment Period. For each week in the Treatment Period, a weekly SBM 3 + 1 responder was a patient who had an SBM weekly rate ≥ 3 and an increase ≥ 1 in the SBM weekly rate from baseline for that week. |
| 8-week treatment period |
| Change From Baseline in 8-Week Stool Consistency | Stool Consistency was assessed using the 7-Point Bristol Stool Form Scale:
| Baseline (Week 0) to Week 8 |
| Change From Baseline in 8-Week Straining | Straining was measured on a 5-point ordinal scale where a value of 1 is "not at all" and a value of 5 is "an extreme amount." | Baseline (Week 0) to Week 8 |
| Change From Baseline in 8-Week Abdominal Bloating | Abdominal bloating was collected daily via IVRS calls and measured using an 11-point numerical rating scale, where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating. | Baseline (Week 0) to Week 8 |
| Foley |
| Alabama |
| 36535 |
| United States |
| Forest Investigative Site 007 | Phoenix | Arizona | 85029 | United States |
| Forest Investigative Site 008 | Tucson | Arizona | 85710 | United States |
| Forest Investigative Site 003 | North Little Rock | Arkansas | 72217 | United States |
| Forest Investigative Site 018 | Anaheim | California | 92801 | United States |
| Forest Investigative Site 014 | Fountain Valley | California | 92708 | United States |
| Forest Investigative Site 019 | Fresno | California | 93702 | United States |
| Forest Investigative Site 017 | Garden Grove | California | 92843 | United States |
| Forest Investigative Site 010 | Gold River | California | 95670 | United States |
| Forest Investigative Site 009 | Lincoln | California | 95648 | United States |
| Forest Investigative Site 012 | North Hollywood | California | 91606 | United States |
| Forest Investigative Site 011 | Orange | California | 92868 | United States |
| Forest Investigative Site 016 | Sacramento | California | 95821 | United States |
| Forest Investigative Site 013 | San Diego | California | 92108 | United States |
| Forest Investigative Site 015 | Santa Ana | California | 92701 | United States |
| Forest Investigative Site 020 | Colorado Springs | Colorado | 80904 | United States |
| Forest Investigative Site 021 | Bristol | Connecticut | 06010 | United States |
| Forest Investigative Site 035 | Boynton Beach | Florida | 33426 | United States |
| Forest Investigative Site 038 | Bradenton | Florida | 34208 | United States |
| Forest Investigative Site 024 | DeLand | Florida | 32720 | United States |
| Forest Investigative Site 027 | Gainesville | Florida | 32607 | United States |
| Forest Investigative Site 023 | Jacksonville | Florida | 32257 | United States |
| Forest Investigative Site 036 | Jupiter | Florida | 33458 | United States |
| Forest Investigative Site 037 | Lauderdale Lakes | Florida | 33319 | United States |
| Forest Investigative Site 028 | Miami | Florida | 33185 | United States |
| Forest Investigative Site 040 | Orlando | Florida | 32801 | United States |
| Forest Investigative Site 022 | Oviedo | Florida | 32765 | United States |
| Forest Investigative Site 034 | Port Orange | Florida | 32129 | United States |
| Forest Investigative Site 029 | Seminole | Florida | 33777 | United States |
| Forest Investigative Site 031 | Tampa | Florida | 33603 | United States |
| Forest Investigative Site 033 | Tampa | Florida | 33606 | United States |
| Forest Investigative Site 030 | Tampa | Florida | 33613 | United States |
| Forest Investigative Site 039 | West Palm Beach | Florida | 33409 | United States |
| Forest Investigative Site 032 | Weston | Florida | 33331 | United States |
| Forest Investigative Site 041 | Marietta | Georgia | 30060 | United States |
| Forest Investigative Site 042 | Woodstock | Georgia | 30189 | United States |
| Forest Investigative Site 043 | Chicago | Illinois | 60616 | United States |
| Forest Investigative Site 044 | Evansville | Indiana | 47714 | United States |
| Forest Investigative Site 045 | Madisonville | Kentucky | 42431 | United States |
| Forest Investigative Site 046 | Metairie | Louisiana | 70006 | United States |
| Forest Investigative Site 048 | Hagerstown | Maryland | 21742 | United States |
| Forest Investigative Site 047 | Watertown | Massachusetts | 02472 | United States |
| Forest Investigative Site 050 | Chesterfield | Michigan | 48047 | United States |
| Forest Investigative Site 049 | Flint | Michigan | 48504 | United States |
| Forest Investigative Site 058 | Omaha | Nebraska | 68114 | United States |
| Forest Investigative Site 057 | Omaha | Nebraska | 68134 | United States |
| Forest Investigative Site 059 | Williamsville | New York | 14221 | United States |
| Forest Investigative Site 082 | Asheboro | North Carolina | 27203 | United States |
| Forest Investigative Site 054 | Chapel Hill | North Carolina | 27514 | United States |
| Forest Investigative Site 088 | Davidson | North Carolina | 28036 | United States |
| Forest Investigative Site 051 | Flat Rock | North Carolina | 28731 | United States |
| Forest Investigative Site 052 | Greensboro | North Carolina | 27403 | United States |
| Forest Investigative Site 055 | Greensboro | North Carolina | 27410 | United States |
| Forest Investigative Site 053 | Winston-Salem | North Carolina | 27103 | United States |
| Forest Investigative Site 056 | Fargo | North Dakota | 58103 | United States |
| Forest Investigative Site 062 | Cincinnati | Ohio | 45219 | United States |
| Forest Investigative Site 061 | Columbus | Ohio | 43213 | United States |
| Forest Investigative Site 060 | Mentor | Ohio | 44060 | United States |
| Forest Investigative Site 087 | Wadsworth | Ohio | 44281 | United States |
| Forest Investigative Site 064 | Oklahoma City | Oklahoma | 73103 | United States |
| Forest Investigative Site 063 | Oklahoma City | Oklahoma | 73120 | United States |
| Forest Investigative Site 065 | Tulsa | Oklahoma | 74104 | United States |
| Forest Investigative Site 066 | Medford | Oregon | 97504 | United States |
| Forest Investigative Site 067 | Levittown | Pennsylvania | 19056 | United States |
| Forest Investigative Site 080 | Philadelphia | Pennsylvania | 19140 | United States |
| Forest Investigative Site 068 | Cumberland | Rhode Island | 02864 | United States |
| Forest Investigative Site 070 | Charleston | South Carolina | 29406 | United States |
| Forest Investigative Site 083 | Richardson | Texas | 75080 | United States |
| Forest Investigative Site 074 | San Antonio | Texas | 78209 | United States |
| Forest Investigative Site 073 | San Antonio | Texas | 78215 | United States |
| Forest Investigative Site 071 | San Antonio | Texas | 78229 | United States |
| Forest Investigative Site 075 | Logan | Utah | 84341 | United States |
| Forest Investigative Site 084 | Ogden | Utah | 84341 | United States |
| Forest Investigative Site 076 | West Jordan | Utah | 84088 | United States |
| Forest Investigative Site 078 | Christiansburg | Virginia | 24073 | United States |
| Forest Investigative Site 079 | Bellevue | Washington | 98007 | United States |
Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. |
| FG002 | Linaclotide 290 Micrograms | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. |
| COMPLETED |
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| NOT COMPLETED |
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Of the 254 participants who were randomized to treatment, 2 patients were randomized in error and did not receive investigational product. 252 of the randomized participants did receive investigational product and comprise the Safety and ITT populations.
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. |
| BG001 | Linaclotide 145 Micrograms | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. |
| BG002 | Linaclotide 290 Micrograms | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | Years |
| |||||||||||||||
| Age, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Sex/Gender, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Weight | Mean | Standard Deviation | kg |
| |||||||||||||||
| Height | Mean | Standard Deviation | cm |
| |||||||||||||||
| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m^2 |
| |||||||||||||||
| SBM Frequency Rate | Number of spontaneous bowel movements (SBMs) per week | Mean | Standard Deviation | SBMs per week |
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| 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 | Change From Baseline in 8-Week SBM Frequency Rate (SBMs/Week) | Change from baseline in 8-Week SBM frequency rate (SBMs/week) during the Treatment Period. | 252 participants received at least one dose of study drug, comprising the ITT study population. | Posted | Least Squares Mean | Standard Error | Number of SBMs per week | Baseline (Week 0) to Week 8 |
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| Secondary | Time to First SBM After the First Dose of Investigational Product | The median time to the first SBM after the first dose of investigational product | 252 participants received at least one dose of study drug, comprising the ITT study population. | Posted | Median | 95% Confidence Interval | hours | Baseline (Day 0) up to 8 weeks |
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| Secondary | Percentage of Participants Meeting 6/8 Week Spontaneous Bowel Movement (SBM) 3 + 1 Responder Criteria | A 6/8 Week SBM 3 + 1 responder was a participant who met the weekly SBM 3 + 1 responder criteria for at least 6 out of the 8 weeks of the Treatment Period. For each week in the Treatment Period, a weekly SBM 3 + 1 responder was a patient who had an SBM weekly rate ≥ 3 and an increase ≥ 1 in the SBM weekly rate from baseline for that week. | 252 participants received at least one dose of study drug, comprising the ITT study population. | Posted | Number | Percentage of Responders | 8-week treatment period |
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| Secondary | Change From Baseline in 8-Week Stool Consistency | Stool Consistency was assessed using the 7-Point Bristol Stool Form Scale:
| Of the 252 participants in the ITT population, 200 participants had Stool Consistency data collected | Posted | Least Squares Mean | Standard Error | Units on a scale | Baseline (Week 0) to Week 8 |
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| Secondary | Change From Baseline in 8-Week Straining | Straining was measured on a 5-point ordinal scale where a value of 1 is "not at all" and a value of 5 is "an extreme amount." | Of the 252 participants in the ITT population, 200 participants had 8-week straining data collected | Posted | Least Squares Mean | Standard Error | Units on a scale | Baseline (Week 0) to Week 8 |
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| Secondary | Change From Baseline in 8-Week Abdominal Bloating | Abdominal bloating was collected daily via IVRS calls and measured using an 11-point numerical rating scale, where 0 represents no abdominal bloating and 10 represents very severe abdominal bloating. | 252 participants received at least one dose of study drug, comprising the ITT study population. | Posted | Least Squares Mean | Standard Error | Units on a scale | Baseline (Week 0) to Week 8 |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. | 1 | 78 | 5 | 78 | 16 | 78 |
| EG001 | Linaclotide 145 Micrograms | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. | 0 | 87 | 0 | 87 | 24 | 87 |
| EG002 | Linaclotide 290 Micrograms | Oral capsule, taken once daily each morning at least 30 minutes before breakfast, with the exception of the first Treatment Period dose which will be taken at the study center after at least a 2-hour fast. | 0 | 87 | 1 | 87 | 33 | 87 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Seizure | Nervous system disorders | MedDRA 18.0 | Systematic Assessment |
| |
| Ankle fracture | Injury, poisoning and procedural complications | MedDRA 18.0 | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA 18.0 | Systematic Assessment |
| |
| Transient Ischaemic Attack | Cardiac disorders | MedDRA 18.0 | Systematic Assessment |
| |
| Cardiac arrest | Cardiac disorders | MedDRA 18.0 | Systematic Assessment |
| |
| Calculus ureteric | Renal and urinary disorders | MedDRA 18.0 | Systematic Assessment |
| |
| Periprosthetic fracture | Injury, poisoning and procedural complications | MedDRA 18.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 18.0 | Systematic Assessment |
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Publication of the results by the Investigator will be subject to mutual agreement between the Investigator, Forest Research Institute, Inc., an affiliate of Allergan, and Ironwood Pharmaceuticals Inc.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Therapeutic Area Head | Forest Research Institute, Inc., an affiliate of Allergan | 862-261-7000 | IR-CTRegistration@allergan.com |
| ID | Term |
|---|---|
| D000079689 | Opioid-Induced Constipation |
| ID | Term |
|---|---|
| D003248 | Constipation |
| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D000079524 | Narcotic-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C523483 | linaclotide |
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| 40 to under 65 |
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| 65 and over |
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| Female |
|
| Black or African American |
|
| Asian |
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| American Indian or Alaska Native |
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| Native Hawaiian or Other Pacific Islander |
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| Multiple Races |
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| Not Hispanic or Latino |
|
| Least squares mean difference |
| 1.908 |
| Standard Error of the Mean |
| 0.451 |
| 2-Sided |
| 95 |
| 1.021 |
| 2.796 |
| Superiority |
| Units | Counts |
|---|---|
| Participants |
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| Units | Counts |
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| Participants |
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