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 (OBD).
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 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 inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase (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
* Opioid dose adjustment (+/- 30%), and/or change in opioid agent or route of administration within 30 days of screening. * Non-ambulatory patients, or those who are unable to eat/drink, take oral medications, or to hold down oral medications due to vomiting. * 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). * Gastrointestinal or abdominal surgical procedures within 90 days prior to screening. * 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Mean Weekly Spontaneous Bowel Movement (SBM) Frequency in Subjects Without Dose Reduction Prior to Week 8 | Baseline and Week 8 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Weekly SBM Frequency | Baseline, Week 12, and Weeks 1-12 | For overall assessment of change, average weekly rating was calculated from data collected from Week 1 through Week 12. |
| First Post-dose SBM | 24 and 48 hours post-dose | The number of participants that experienced first post-dose SBM 24 and 48 hour of dose initiation. |
| Responder Rate | Up to 12 weeks | Number of participants, who remained on treatment for at least 8 weeks, and reported response (\>=3 SBMs) for at least 50% of weeks on study. |
| Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Weeks 1-12 | Ratings over 12-week treatment period were averaged and difference from baseline score calculated Straining scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe Stool consistency scale: 0 = very loose, 1 = loose, 2 = normal, 3 = hard, 4 = very hard (little balls) Constipation severity scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe Abdominal bloating scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe Abdominal discomfort scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe Bowel habit regularity scale: 7-point scale, where 1 = very regular and 7 = very irregular |
| Treatment Effectiveness | Weeks 1-12 | Treatment effectiveness scale: 0 = not at all effective, 1 = a little bit effective, 2 = moderately effective, 3 = quite a bit effective, 4 = extremely effective |
Countries
Canada, United States
Participant flow
Recruitment details
Recruitment period: 06 August 2007 through 06 March 2009 Recruitment sites: 84 U.S. investigative sites and 4 Canadian investigative sites
Pre-assignment details
Safety evaluable population (listed below under 'Started') includes all subjects who randomized and dosed. NOTE: these numbers are based on 1 miss randomized subjects - randomized to Lubiprostone and received Placebo. ITT population includes only those subjects who dosed and provided at least one post-treatment efficacy assessment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo : 0 mcg capsules twice daily (BID) | 212 |
| Lubiprostone Lubiprostone : 24 mcg capsules twice daily (BID) | 223 |
| Total | 435 |
Baseline characteristics
| Characteristic | Placebo | Lubiprostone | Total |
|---|---|---|---|
| Age, Continuous | 49.8 years STANDARD_DEVIATION 10.44 | 48.9 years STANDARD_DEVIATION 9.85 | 49.4 years STANDARD_DEVIATION 10.14 |
| Region of Enrollment Canada | 5 participants | 4 participants | 9 participants |
| Region of Enrollment United States | 207 participants | 219 participants | 426 participants |
| Sex: Female, Male Female | 126 Participants | 140 Participants | 266 Participants |
| Sex: Female, Male Male | 86 Participants | 83 Participants | 169 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 214 | 49 / 223 |
| serious Total, serious adverse events | 7 / 214 | 7 / 223 |
Outcome results
Primary
Change From Baseline in Mean Weekly Spontaneous Bowel Movement (SBM) Frequency in Subjects Without Dose Reduction Prior to Week 8
Time frame: Baseline and Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Weekly Spontaneous Bowel Movement (SBM) Frequency in Subjects Without Dose Reduction Prior to Week 8 | 2.4 Spontaneous Bowel Movements/Week | Standard Deviation 3.2 |
| Lubiprostone | Change From Baseline in Mean Weekly Spontaneous Bowel Movement (SBM) Frequency in Subjects Without Dose Reduction Prior to Week 8 | 2.6 Spontaneous Bowel Movements/Week | Standard Deviation 3.26 |
Secondary
Change From Baseline in Mean Weekly SBM Frequency
For overall assessment of change, average weekly rating was calculated from data collected from Week 1 through Week 12.
Time frame: Baseline, Week 12, and Weeks 1-12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Mean Weekly SBM Frequency | Week 12 | 2.6 Spontaneous Bowel Movements/Week | Standard Deviation 3.57 |
| Placebo | Change From Baseline in Mean Weekly SBM Frequency | Overall | 2.3 Spontaneous Bowel Movements/Week | Standard Deviation 2.57 |
| Lubiprostone | Change From Baseline in Mean Weekly SBM Frequency | Week 12 | 2.5 Spontaneous Bowel Movements/Week | Standard Deviation 3.64 |
| Lubiprostone | Change From Baseline in Mean Weekly SBM Frequency | Overall | 2.6 Spontaneous Bowel Movements/Week | Standard Deviation 2.73 |
Secondary
First Post-dose SBM
The number of participants that experienced first post-dose SBM 24 and 48 hour of dose initiation.
Time frame: 24 and 48 hours post-dose
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | First Post-dose SBM | 24 hours | 64 participants |
| Placebo | First Post-dose SBM | 48 hours | 118 participants |
| Lubiprostone | First Post-dose SBM | 24 hours | 74 participants |
| Lubiprostone | First Post-dose SBM | 48 hours | 136 participants |
Secondary
Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity
Ratings over 12-week treatment period were averaged and difference from baseline score calculated Straining scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe Stool consistency scale: 0 = very loose, 1 = loose, 2 = normal, 3 = hard, 4 = very hard (little balls) Constipation severity scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe Abdominal bloating scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe Abdominal discomfort scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe Bowel habit regularity scale: 7-point scale, where 1 = very regular and 7 = very irregular
Time frame: Weeks 1-12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Straining | -0.5 units on a scale | Standard Deviation 0.89 |
| Placebo | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Stool consistency | -0.4 units on a scale | Standard Deviation 0.81 |
| Placebo | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Constipation severity | -0.5 units on a scale | Standard Deviation 0.72 |
| Placebo | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Abdominal bloating | -0.4 units on a scale | Standard Deviation 0.64 |
| Placebo | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Abdominal discomfort | -0.4 units on a scale | Standard Deviation 0.64 |
| Placebo | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Bowel habit regularity | -0.6 units on a scale | Standard Deviation 1.57 |
| Lubiprostone | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Abdominal discomfort | -0.5 units on a scale | Standard Deviation 0.69 |
| Lubiprostone | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Straining | -0.8 units on a scale | Standard Deviation 0.96 |
| Lubiprostone | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Abdominal bloating | -0.5 units on a scale | Standard Deviation 0.7 |
| Lubiprostone | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Stool consistency | -0.6 units on a scale | Standard Deviation 0.84 |
| Lubiprostone | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Bowel habit regularity | -0.8 units on a scale | Standard Deviation 1.57 |
| Lubiprostone | Mean Changes From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity | Constipation severity | -0.6 units on a scale | Standard Deviation 0.79 |
Secondary
Responder Rate
Number of participants, who remained on treatment for at least 8 weeks, and reported response (\>=3 SBMs) for at least 50% of weeks on study.
Time frame: Up to 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Responder Rate | 100 participants |
| Lubiprostone | Responder Rate | 108 participants |
Secondary
Treatment Effectiveness
Treatment effectiveness scale: 0 = not at all effective, 1 = a little bit effective, 2 = moderately effective, 3 = quite a bit effective, 4 = extremely effective
Time frame: Weeks 1-12
Population: Treatment effectiveness scores were collected at the end of each treatment week during the study; the number of participants analyzed reflects those subjects who provided at least one end-of-week assessment of treatment effectiveness. For the analysis, treatment effectiveness scores were averaged across the treatment period (Weeks 1-12).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Treatment Effectiveness | 1.4 units on a scale | Standard Deviation 1.04 |
| Lubiprostone | Treatment Effectiveness | 1.5 units on a scale | Standard Deviation 1.07 |