Opioid-induced Constipation
Conditions
Keywords
Opioid-induced Constipation
Brief summary
The purpose of this study is to evaluate the efficacy and safety of naldemedine in the treatment of opioid-induced constipation (OIC) in adults with non-malignant chronic pain who are not using laxatives.
Interventions
DRUGNaldemedine
Naldemedine 0.2 mg tablet taken orally once a day
DRUGPlacebo
Placebo tablet taken orally once a day
Sponsors
Shionogi
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Subjects aged 18 to 80 years inclusive at the time of informed consent * Subjects must have non-malignant chronic pain treated with opioids and must have opioid-induced constipation (OIC) * Subjects must be treated with a stable opioid regimen at a total daily dose on average of ≥ 30 mg equivalents of oral morphine sulfate * Subjects must not be currently using laxatives or must be willing to discontinue laxative use at Screening and must be willing to use only the rescue laxatives provided throughout the study duration * Subjects must meet opioid-induced constipation criteria based on the Bowel Movement and Constipation Assessment (BMCA) Diary
Exclusion criteria
* Evidence of significant structural abnormalities of the gastrointestinal (GI) tract * Evidence of active medical diseases affecting bowel transit * History or presence of pelvic disorders that may be a cause of constipation * Surgery (except for minor procedures) within 60 days of Screening * History of chronic constipation prior to starting analgesic medication or any potential non-opioid cause of bowel dysfunction that may be a major contributor to the constipation (e.g., mechanical GI obstruction) * Subjects who have never taken laxatives for the treatment of OIC * History of active treatment for cancer within the last 2 years (except for basal cell or squamous cell carcinoma of the skin that have been successfully resected) or tamoxifen \[Nolvadex®\] and raloxifene \[Evista®\] when being used for prevention of breast cancer * Current use of any prohibited medication including opioid antagonists, partial agonists, or mixed agonists/antagonists
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Spontaneous Bowel Movement (SBM) Response | 12-week treatment period | A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of rescue laxative therapy during the 24 hours prior to the BM. A responder was defined as a participant having 9 or more positive response weeks out of the 12-week Treatment Period and 3 positive response weeks out of last 4 weeks of the 12-week Treatment Period. A positive response week was defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week. If a participant had less than 4 days of diary entries for a week, that week was treated as a non-response week. Any participant with insufficient primary endpoint data (data for less than 9 out of the 12 weeks of the Treatment Period or less than 3 out of the last 4 weeks of the 12-week Treatment Period) was treated as a non-responder |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week | Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment) | A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration. |
| Change From Baseline to Week 1 in the Number of Spontaneous Bowel Movements Per Week | Baseline and Week 1 | A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration. |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements Per Week | Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment) | A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. A complete spontaneous bowel movement (CSBM) was defined as an SBM which was accompanied by the feeling of complete evacuation. |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements With No Straining Per Week | Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment) | A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. The severity of straining with each bowel movement was assessed on the following scale: 0=no straining, 1=mild straining, 2=moderate straining, 3=severe straining, 4=very severe straining. SBMs without straining were defined as SBMs with a straining score of 0. |
Countries
United States
Participant flow
Recruitment details
Participants were randomized at 69 sites in North America and Europe, including Austria, Czech Republic, Germany, Poland, Spain, and the United States.
Pre-assignment details
Participants were randomized in a 1:1 ratio to 0.2 mg naldemedine or placebo for 12 weeks. Randomization was stratified based on documented opioid use (average total daily dose (TDD) during the 14-consecutive-day qualifying period) as follows: * 30 to 100 mg equivalents of oral morphine sulfate * \> 100 mg equivalents of oral morphine sulfate
Participants by arm
| Arm | Count |
|---|---|
| Naldemedine Participants received 0.2 mg naldemedine orally once daily for 12 weeks. | 276 |
| Placebo Participants received placebo orally once daily for 12 weeks. | 274 |
| Total | 550 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 16 | 11 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 5 |
| Overall Study | Other - Miscellaneous | 1 | 1 |
| Overall Study | Protocol Violation | 5 | 8 |
| Overall Study | Withdrawal by Subject | 15 | 19 |
Baseline characteristics
| Characteristic | Naldemedine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 54.1 Years STANDARD_DEVIATION 10.48 | 52.9 Years STANDARD_DEVIATION 11.4 | 53.5 Years STANDARD_DEVIATION 10.96 |
| Age, Customized ≥ 40 to < 65 years | 210 participants | 196 participants | 406 participants |
| Age, Customized < 40 years | 22 participants | 40 participants | 62 participants |
| Age, Customized ≥ 65 years | 44 participants | 38 participants | 82 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 27 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 250 Participants | 247 Participants | 497 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 participants | 4 participants | 7 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 3 participants | 5 participants |
| Race/Ethnicity, Customized Black or African American | 49 participants | 39 participants | 88 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 222 participants | 227 participants | 449 participants |
| Sex: Female, Male Female | 165 Participants | 168 Participants | 333 Participants |
| Sex: Female, Male Male | 111 Participants | 106 Participants | 217 Participants |
| Spontaneous Bowel Movements per Week | 1.16 spontaneous bowel movements / week STANDARD_DEVIATION 0.755 | 1.17 spontaneous bowel movements / week STANDARD_DEVIATION 0.73 | 1.17 spontaneous bowel movements / week STANDARD_DEVIATION 0.742 |
| Stratification by Opioid Dose > 100 mg | 107 participants | 107 participants | 214 participants |
| Stratification by Opioid Dose 30-100 mg | 169 participants | 167 participants | 336 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 271 | 20 / 274 |
| serious Total, serious adverse events | 9 / 271 | 13 / 274 |
Outcome results
Primary
Percentage of Participants With a Spontaneous Bowel Movement (SBM) Response
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of rescue laxative therapy during the 24 hours prior to the BM. A responder was defined as a participant having 9 or more positive response weeks out of the 12-week Treatment Period and 3 positive response weeks out of last 4 weeks of the 12-week Treatment Period. A positive response week was defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week. If a participant had less than 4 days of diary entries for a week, that week was treated as a non-response week. Any participant with insufficient primary endpoint data (data for less than 9 out of the 12 weeks of the Treatment Period or less than 3 out of the last 4 weeks of the 12-week Treatment Period) was treated as a non-responder
Time frame: 12-week treatment period
Population: Intent-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Naldemedine | Percentage of Participants With a Spontaneous Bowel Movement (SBM) Response | 52.5 percentage of participants |
| Placebo | Percentage of Participants With a Spontaneous Bowel Movement (SBM) Response | 33.6 percentage of participants |
p-value: <0.000195% CI: [10.8, 27]Cochran-Mantel-Haenszel
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements Per Week
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. A complete spontaneous bowel movement (CSBM) was defined as an SBM which was accompanied by the feeling of complete evacuation.
Time frame: Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)
Population: Intent-to-treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naldemedine | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements Per Week | 2.77 complete spontaneous BMs / week | Standard Error 0.166 |
| Placebo | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements Per Week | 1.62 complete spontaneous BMs / week | Standard Error 0.166 |
p-value: <0.000195% CI: [0.7, 1.61]ANCOVA
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration.
Time frame: Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)
Population: Intent-to-treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naldemedine | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week | 3.56 spontaneous bowel movements / week | Standard Error 0.174 |
| Placebo | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week | 2.16 spontaneous bowel movements / week | Standard Error 0.174 |
p-value: <0.000195% CI: [0.92, 1.88]ANCOVA
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements With No Straining Per Week
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. The severity of straining with each bowel movement was assessed on the following scale: 0=no straining, 1=mild straining, 2=moderate straining, 3=severe straining, 4=very severe straining. SBMs without straining were defined as SBMs with a straining score of 0.
Time frame: Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)
Population: Intent-to-treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naldemedine | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements With No Straining Per Week | 1.85 SBMs with no straining / week | Standard Error 0.163 |
| Placebo | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements With No Straining Per Week | 1.10 SBMs with no straining / week | Standard Error 0.162 |
p-value: 0.001195% CI: [0.3, 1.19]ANCOVA
Secondary
Change From Baseline to Week 1 in the Number of Spontaneous Bowel Movements Per Week
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration.
Time frame: Baseline and Week 1
Population: Intent-to-treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Naldemedine | Change From Baseline to Week 1 in the Number of Spontaneous Bowel Movements Per Week | 3.86 spontaneous bowel movements / week | Standard Error 0.199 |
| Placebo | Change From Baseline to Week 1 in the Number of Spontaneous Bowel Movements Per Week | 1.69 spontaneous bowel movements / week | Standard Error 0.198 |
p-value: <0.000195% CI: [1.63, 2.71]ANCOVA