Opioid-induced Constipation
Conditions
Brief summary
The purpose of this study is to examine the safety and activity of MNTX in relieving opioid-induced constipation following orthopedic procedures.
Detailed description
This is a double-blind, randomized, parallel-group, placebo- controlled Phase 2 study to evaluate the safety and activity of subcutaneous (SC) MNTX versus SC placebo in participants who have undergone orthopedic procedures and who are expected to require opioids for 1 week after randomization. Participants will sign an informed consent form and be screened between Days 4-10 after their orthopedic procedure. Those participants who meet all eligibility requirements will be enrolled in the study. Treatment with study medication will be continued until either the participant no longer requires opioid medication for pain relief or the maximum number of doses is reached. Originally, participants were receiving treatment for up to 7 days. Then after Protocol Amendment 1 (12 March 2008), the duration of treatment changed from up to 7 days to up to 4 days.
Interventions
Methylnaltrexone will be administered as per the dose and schedule specified in the respective arm.
DRUGPlacebo
Placebo matching to methylnaltrexone will be administered as per the dose and schedule specified in the respective arm.
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
Bausch Health Americas, 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
1. Male and female participants greater than or equal to (\>=) 18 years of age. 2. Participants must have undergone an orthopedic procedure (that is, total knee or hip replacement, spinal fusion, or reduction of fracture(s) with or without surgical fixation post trauma). 3. Participants must be receiving opioid analgesics (a mu agonist only-not to include agents with mixed mechanisms of action such as tramadol or buprenorphine) after the procedures and be expected to require daily opioid analgesics for at least 7 days post randomization. 4. Participants must be acutely constipated following their orthopedic procedure. 5. Participants must receive all doses of study drug in either hospitals or rehabilitation facilities. 6. Participants must sign an informed consent form. 7. Females of childbearing potential must have a negative pregnancy test and use appropriate birth control throughout the study. 8. Body weight within range of 40 kilograms (kg) - 150 kg (88 - 330 pounds \[lbs\]).
Exclusion criteria
1. Participants with known hypersensitivity to methylnaltrexone, naltrexone, or naloxone. 2. Participants who received any investigational new drug (experimental) in the previous 30 days. 3. Participants who have received a laxative (for example, lactulose) or an enema within 48 hours prior to the first dose. 4. Participants with constipation not attributed to post procedure opioids. 5. Participants with a history of alcohol or prescription or non-prescription drug abuse within the past 2 years. 6. Female participants who are pregnant or lactating. 7. Participants with a known history of chronic active hepatitis B or hepatitis C virus or human immunodeficiency virus (HIV) infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Laxation Response Within 2 Hours of the First Dose | 2 hours | Percentage of participants who had a laxation (that is, bowel movement) within 2 hours after the first dose of study drug, were reported. Participants taking stool softeners within 24 hours of study drug dosing and participants taking rescue laxative medications within 48 hours of study drug dosing were assessed as treatment failures. |
| Percentage of Participants With Laxation Response Within 4 Hours of the First Dose | 4 hours | Percentage of participants who had a laxation (that is, bowel movement) within 4 hours after the first dose of study drug, were reported. Participants taking stool softeners within 24 hours of study drug dosing and participants taking rescue laxative medications within 48 hours of study drug dosing were assessed as treatment failures. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Rescue-Free Bowel Movement (Laxation) | Baseline (Day 1) up to Day 4 or 7 | A rescue-free laxation was defined as a laxation without use of any rescue medication or rescue procedures. Time to first rescue-free bowel movement following the first dose of study drug was reported. |
Countries
United States
Participant flow
Pre-assignment details
A total of 37 participants were randomized in 1:1 ratio to receive either methylnaltrexone (MNTX) or placebo. Originally, participants were receiving treatment for up to 7 days. Then, after Protocol Amendment 1 (12 March 2008), the duration of treatment was changed from up to 7 days to up to 4 days.
Participants by arm
| Arm | Count |
|---|---|
| MNTX Participants received MNTX 12 mg SC once daily for up to 4 or 7 days, depending upon the protocol version under which each participant was enrolled. | 18 |
| Placebo Participants received placebo matched to MNTX SC once daily for up to 4 or 7 days, depending upon the protocol version under which each participant was enrolled. | 15 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Randomized but not treated | 1 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | MNTX | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 9.04 | 65.2 years STANDARD_DEVIATION 11.56 | 64.7 years STANDARD_DEVIATION 10.11 |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 22 Participants |
| Sex: Female, Male Male | 7 Participants | 4 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 18 | 4 / 15 |
| serious Total, serious adverse events | 0 / 18 | 0 / 15 |
Outcome results
Primary
Percentage of Participants With Laxation Response Within 2 Hours of the First Dose
Percentage of participants who had a laxation (that is, bowel movement) within 2 hours after the first dose of study drug, were reported. Participants taking stool softeners within 24 hours of study drug dosing and participants taking rescue laxative medications within 48 hours of study drug dosing were assessed as treatment failures.
Time frame: 2 hours
Population: MITT population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MNTX | Percentage of Participants With Laxation Response Within 2 Hours of the First Dose | 33.33 percentage of participants |
| Placebo | Percentage of Participants With Laxation Response Within 2 Hours of the First Dose | 0 percentage of participants |
Comparison: Analysis was performed using Fisher exact test comparing the percentage of participants with a laxation response within 2 hours of the first dose of study drug, testing MNTX against placebo.p-value: 0.0213Fisher Exact
Primary
Percentage of Participants With Laxation Response Within 4 Hours of the First Dose
Percentage of participants who had a laxation (that is, bowel movement) within 4 hours after the first dose of study drug, were reported. Participants taking stool softeners within 24 hours of study drug dosing and participants taking rescue laxative medications within 48 hours of study drug dosing were assessed as treatment failures.
Time frame: 4 hours
Population: MITT population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MNTX | Percentage of Participants With Laxation Response Within 4 Hours of the First Dose | 38.89 percentage of participants |
| Placebo | Percentage of Participants With Laxation Response Within 4 Hours of the First Dose | 6.67 percentage of participants |
Comparison: Analysis was performed using Fisher exact test comparing the percentage of participants with a laxation response within 4 hours of the first dose of study drug, testing MNTX against placebo.p-value: 0.0463Fisher Exact
Secondary
Time to First Rescue-Free Bowel Movement (Laxation)
A rescue-free laxation was defined as a laxation without use of any rescue medication or rescue procedures. Time to first rescue-free bowel movement following the first dose of study drug was reported.
Time frame: Baseline (Day 1) up to Day 4 or 7
Population: MITT population included all randomized participants who received at least 1 dose of study drug. One participant with bowel movement prior to dosing was excluded from placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MNTX | Time to First Rescue-Free Bowel Movement (Laxation) | 23.8 hours | Standard Error 6.3 |
| Placebo | Time to First Rescue-Free Bowel Movement (Laxation) | 46.7 hours | Standard Error 6.49 |