Opioid-Induced Bowel Dysfunction
Conditions
Brief summary
The primary purpose of this study is to evaluate the efficacy and safety of lubiprostone administration in patients with Opioid-induced Bowel Dysfunction.
Interventions
DRUGLubiprostone
24 mcg capsules twice daily (BID)
DRUGPlacebo
0 mcg capsules twice daily (BID)
Sponsors
Sucampo Pharmaceuticals, Inc.
Sucampo Pharma Americas, LLC
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
* Consistent treatment for chronic, non-cancer-related pain with any full agonist opioid for at least 30 days prior to screening. * Diagnosis of opioid-induced bowel dysfunction (OBD) as confirmed during the screening period. * If patient has a history of chronic constipation, condition must have been exacerbated by initiation of opioid treatment. * Use of prescribed or Over-the-Counter (OTC) medication that affects gastrointestinal motility (other than opioid therapy) must be discontinued during the study. * If treated for clinical depression with Selective serotonin reuptake inhibitor (SSRIs), Serotonin-norepinephrine reuptake inhibitor (SNRIs), or Monoamine oxidase inhibitor (MAO) inhibitors, treatment must have been at a stable dose for at least 30 days prior to screening. * Use of laxative and stool softeners (with the exception of approved rescue medications) must be discontinued while on study.
Exclusion criteria
* Treatment with opioid therapy for cancer-related pain, abdominal pain, scleroderma, and/or for the management of drug addiction. * Patient has been treated for cancer in the past 5 years (with the exception of localized basal cell, squamous cell skin cancer, or in situ cancer that has been resected). * Opioid dose adjustment (+/- 30%), and/or change in opioid agent or route of administration within 30 days of screening. * Gastrointestinal or abdominal surgical procedures within 90 days prior to screening. * Non-ambulatory patients, or those who are unable to eat/drink, take oral medications, or to hold down oral medications due to vomiting. * Female patients of childbearing potential who are unable/unwilling to use protocol-specified method(s) of birth control and/or are pregnant, nursing, or plan to become pregnant or nurse during the study. * Prior use of Amitiza, lubiprostone, SPI-0211, or RU-0211.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Weekly Spontaneous Bowel Movements at Week 8 | at Week 8 | Spontaneous bowel movements (SBMs) are defined as bowel movements without the aid of drugs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Spontaneous Bowel Movements (SBM) Per Week Within 12 Weeks | within 12 weeks | Average weekly SBM frequency was calculated from data collected from Week 1 through Week 12 |
| Number of Participants With the First Post-dose Spontaneous Bowel Movement Within 48 Hours Post-dose | within 48 hours post-dose | The number of participants who experienced their first post-dose Spontaneous Bowel Movement within 24 and 48 hours after dosing started. |
| Number of Participants Classified as Responders | within 12 weeks | Number of participants who remained on treatment for at least 8 weeks, and reported at least 3 SBMs for at least half the weeks on study. |
| Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | within 12 weeks | Measures collected over 12-week treatment period were averaged, and the score at baseline was subtracted from the score at week 12 to determine the change from baseline. Straining scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Stool consistency scale: 0 = very loose, 1 = loose, 2 = normal, 3 = hard, 4 = very hard (little balls) - middle scores are best; Constipation severity scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Abdominal bloating scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Abdominal discomfort scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Bowel habit regularity scale: 7-point scale, where 1 = very regular and 7 = very irregular - higher scores are worse |
| Participant Reported Outcome of Treatment Effectiveness | within 12 weeks | Participants rated treatment effectiveness at the end of each treatment week during the study on a 5-point scale, where 0 = not at all effective, 1 = a little bit effective, 2 = moderately effective, 3 = quite a bit effective, 4 = extremely effective. The 12 weekly scores were averaged. Higher scores mean the drug was more effective. |
Countries
Canada, United States
Participant flow
Recruitment details
Recruitment period: 03 August 2007 to 06 March 2009 Recruitment sites: 77 U.S. investigative sites and 3 Canadian investigative sites
Pre-assignment details
Safety evaluable population, defined as all participants who were randomized and dosed, according to the product actually received.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo : 0 mcg capsules twice daily (BID) | 217 |
| Lubiprostone Lubiprostone : 24 mcg capsules twice daily (BID) | 221 |
| Total | 438 |
Baseline characteristics
| Characteristic | Placebo | Lubiprostone | Total |
|---|---|---|---|
| Age, Continuous | 49.9 years STANDARD_DEVIATION 11.94 | 50.1 years STANDARD_DEVIATION 9.89 | 50.0 years STANDARD_DEVIATION 10.94 |
| Region of Enrollment Canada | 1 participants | 3 participants | 4 participants |
| Region of Enrollment United States | 216 participants | 218 participants | 434 participants |
| Sex: Female, Male Female | 144 Participants | 136 Participants | 280 Participants |
| Sex: Female, Male Male | 73 Participants | 85 Participants | 158 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 218 | 0 / 221 |
| other Total, other adverse events | 22 / 218 | 59 / 221 |
| serious Total, serious adverse events | 8 / 218 | 12 / 221 |
Outcome results
Primary
Mean Weekly Spontaneous Bowel Movements at Week 8
Spontaneous bowel movements (SBMs) are defined as bowel movements without the aid of drugs.
Time frame: at Week 8
Population: Per protocol population at Week 8 without dose reduction
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Weekly Spontaneous Bowel Movements at Week 8 | 2.4 SBMs/Week | Standard Deviation 3.25 |
| Lubiprostone | Mean Weekly Spontaneous Bowel Movements at Week 8 | 3.2 SBMs/Week | Standard Deviation 3.35 |
Secondary
Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity
Measures collected over 12-week treatment period were averaged, and the score at baseline was subtracted from the score at week 12 to determine the change from baseline. Straining scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Stool consistency scale: 0 = very loose, 1 = loose, 2 = normal, 3 = hard, 4 = very hard (little balls) - middle scores are best; Constipation severity scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Abdominal bloating scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Abdominal discomfort scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Bowel habit regularity scale: 7-point scale, where 1 = very regular and 7 = very irregular - higher scores are worse
Time frame: within 12 weeks
Population: Intention to Treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Stool consistency | -0.5 score on a scale | Standard Deviation 0.77 |
| Placebo | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Abdominal bloating | -0.4 score on a scale | Standard Deviation 0.63 |
| Placebo | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Straining | -0.6 score on a scale | Standard Deviation 0.88 |
| Placebo | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Constipation severity | -0.4 score on a scale | Standard Deviation 0.71 |
| Placebo | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Bowel habit regularity | -0.5 score on a scale | Standard Deviation 1.63 |
| Placebo | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Abdominal discomfort | -0.3 score on a scale | Standard Deviation 0.63 |
| Lubiprostone | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Bowel habit regularity | -0.6 score on a scale | Standard Deviation 1.45 |
| Lubiprostone | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Straining | -1.0 score on a scale | Standard Deviation 1 |
| Lubiprostone | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Stool consistency | -0.8 score on a scale | Standard Deviation 0.91 |
| Lubiprostone | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Constipation severity | -0.6 score on a scale | Standard Deviation 0.74 |
| Lubiprostone | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Abdominal bloating | -0.4 score on a scale | Standard Deviation 0.63 |
| Lubiprostone | Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Abdominal discomfort | -0.5 score on a scale | Standard Deviation 0.62 |
Secondary
Mean Number of Spontaneous Bowel Movements (SBM) Per Week Within 12 Weeks
Average weekly SBM frequency was calculated from data collected from Week 1 through Week 12
Time frame: within 12 weeks
Population: Intention to treat with scores at all 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Number of Spontaneous Bowel Movements (SBM) Per Week Within 12 Weeks | at Week 12 | 2.2 SBMs/Week | Standard Deviation 3.26 |
| Placebo | Mean Number of Spontaneous Bowel Movements (SBM) Per Week Within 12 Weeks | within 12 weeks | 2.1 SBMs/Week | Standard Deviation 2.35 |
| Lubiprostone | Mean Number of Spontaneous Bowel Movements (SBM) Per Week Within 12 Weeks | within 12 weeks | 2.7 SBMs/Week | Standard Deviation 2.59 |
| Lubiprostone | Mean Number of Spontaneous Bowel Movements (SBM) Per Week Within 12 Weeks | at Week 12 | 2.8 SBMs/Week | Standard Deviation 3.6 |
Secondary
Number of Participants Classified as Responders
Number of participants who remained on treatment for at least 8 weeks, and reported at least 3 SBMs for at least half the weeks on study.
Time frame: within 12 weeks
Population: Intention to Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Classified as Responders | 87 Participants |
| Lubiprostone | Number of Participants Classified as Responders | 103 Participants |
Secondary
Number of Participants With the First Post-dose Spontaneous Bowel Movement Within 48 Hours Post-dose
The number of participants who experienced their first post-dose Spontaneous Bowel Movement within 24 and 48 hours after dosing started.
Time frame: within 48 hours post-dose
Population: Intention to treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With the First Post-dose Spontaneous Bowel Movement Within 48 Hours Post-dose | within 24 hours | 65 Participants |
| Placebo | Number of Participants With the First Post-dose Spontaneous Bowel Movement Within 48 Hours Post-dose | within 48 hours | 116 Participants |
| Lubiprostone | Number of Participants With the First Post-dose Spontaneous Bowel Movement Within 48 Hours Post-dose | within 24 hours | 89 Participants |
| Lubiprostone | Number of Participants With the First Post-dose Spontaneous Bowel Movement Within 48 Hours Post-dose | within 48 hours | 138 Participants |
Secondary
Participant Reported Outcome of Treatment Effectiveness
Participants rated treatment effectiveness at the end of each treatment week during the study on a 5-point scale, where 0 = not at all effective, 1 = a little bit effective, 2 = moderately effective, 3 = quite a bit effective, 4 = extremely effective. The 12 weekly scores were averaged. Higher scores mean the drug was more effective.
Time frame: within 12 weeks
Population: Intention to Treat with all required scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Participant Reported Outcome of Treatment Effectiveness | 1.3 score on a scale | Standard Deviation 0.99 |
| Lubiprostone | Participant Reported Outcome of Treatment Effectiveness | 1.6 score on a scale | Standard Deviation 1.04 |