Post-Operative Ileus (POI)
Conditions
Brief summary
To evaluate the safety and efficacy of MNTX in participants who have undergone segmental colectomy and to assess if the time between the end of surgery and the first bowel movement is significantly shorter in the MNTX regimen than the equivalent assessment using a placebo regimen.
Interventions
DRUGMethylnaltrexone
Methylnaltrexone will be administered as per the dose and schedule specified in the respective arms.
DRUGPlacebo
Placebo matching to methylnaltrexone will be administered as per the 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
* Male and female participants at least 18 years of age. * All participants must meet American Society of Anesthesiologists (ASA) physical status I, II, or III. * Participants must sign an informed consent form (ICF). * Participants must be scheduled for a segmental colectomy via open laparotomy with general anesthesia. * Females of childbearing potential must have a negative serum pregnancy test at the screening visit. * Negative for history of chronic active hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV) infection.
Exclusion criteria
* Participants who received any investigational new drug in the 30 days prior to screening visit. * Females who are pregnant or lactating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Bowel Movement | Day 1 (From the time of end of surgery [that is; from the first dose of study drug administration]) up to Day 10 | Time to first bowel movement was measured from the end of surgery (defined as the time when the last skin suture or staple was placed in the participant). Time of the first bowel movement was recorded on the electronic case report form (eCRF). The first bowel movement was defined as a normal stool for a postoperative participant based on the clinical judgment of the investigator or designee. Analysis was performed by Kaplan-Meier estimate. Participants who had a bowel movement but were readmitted to the hospital within 1 week after discharge with a diagnosis of postoperative ileus (POI) were considered censored at the time of the first bowel movement as if the bowel movement had not occurred. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Discharge Eligibility | Day 1 (From the time of end of surgery [that is; from the first dose of study drug administration]) up to Day 10 | Time to discharge eligibility was measured from the end of surgery (defined as the time when the last skin suture or staple was placed in the participant). Discharge eligibility was defined as both tolerance of solid food and at least one bowel movement. Participants were considered to have tolerated solid food when they have eaten greater than or equal to (≥) 50 percent (%), of the first of two successive solid food meals (based on the judgement of the investigator or designee), without vomiting or nausea. Participants readmitted to the hospital with a diagnosis of POI within 7 days of discharge were considered treatment failures. Analysis was performed by Kaplan-Meier estimate. |
| Time to Discharge Order Written From the End of Surgery | Day 1 (From the time of end of surgery [that is; from the first dose of study drug administration]) up to Day 10 | The investigator or designee recorded the time of the order. Participants re-admitted to the hospital with a diagnosis of POI within 7 days after discharge were considered treatment failures. Analysis was performed by Kaplan-Meier estimate. |
| Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at 0 or 24 Hours as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | 0 and 24 hours | CMEs were defined using opioid-related SDS (assessed participant-reported levels of severity concerning 10 symptoms associated with opioid medication usage: fatigue, drowsiness, inability to concentrate, nausea, dizziness, constipation, itching, difficulty with urination, confusion and retching/vomiting). CME = any symptom rated as severe (3) or very severe (4), with the exception of confusion. A total CME score was calculated by summing the number of CMEs across symptoms and ranged from 0 to 9. CME was counted for either nausea or vomiting/retching, or both and reported in this outcome measure. |
Countries
United States
Participant flow
Pre-assignment details
Postoperative participants (who underwent segmental colectomy via open laparotomy) were randomized in 1:1:1 ratio to MNTX 12 mg, MNTX 24 mg, or placebo treatment groups. Randomization was based on regional stratification.
Participants by arm
| Arm | Count |
|---|---|
| MNTX 12 mg Participants received MNTX 12 mg as an IV infusion over approximately 20 minutes for every 6 hours until one of the following occurred: 1) 24 hours elapsed after the first bowel movement and the participant was tolerating clear liquids, 2) the participant was discharged from the hospital, or 3) a maximum of 10 days elapsed. The first dose of study drug was administered within the first 90 minutes after the end of surgery (defined as the time when the last skin suture or staple was placed in the participant). | 171 |
| MNTX 24 mg Participants received MNTX 24 mg as an IV infusion over approximately 20 minutes for every 6 hours until one of the following occurred: 1) 24 hours elapsed after the first bowel movement and the participant was tolerating clear liquids, 2) the participant was discharged from the hospital, or 3) a maximum of 10 days elapsed. The first dose of study drug was administered within the first 90 minutes after the end of surgery (defined as the time when the last skin suture or staple was placed in the participant). | 173 |
| Placebo Participants received placebo matched to MNTX as an IV infusion over approximately 20 minutes for every 6 hours until one of the following occurred: 1) 24 hours elapsed after the first bowel movement and the participant was tolerating clear liquids, 2) the participant was discharged from the hospital, or 3) a maximum of 10 days elapsed. The first dose of study drug was administered within the first 90 minutes after the end of surgery (defined as the time when the last skin suture or staple was placed in the participant). | 171 |
| Total | 515 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 11 | 10 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 |
| Overall Study | Other than specified | 2 | 1 | 3 |
| Overall Study | Protocol Violation | 2 | 2 | 1 |
| Overall Study | Randomized but not treated | 3 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 9 | 7 | 7 |
Baseline characteristics
| Characteristic | MNTX 12 mg | MNTX 24 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 56.6 years STANDARD_DEVIATION 15.5 | 58.2 years STANDARD_DEVIATION 15.6 | 58.1 years STANDARD_DEVIATION 15.6 | 57.7 years STANDARD_DEVIATION 15.6 |
| Sex: Female, Male Female | 79 Participants | 71 Participants | 77 Participants | 227 Participants |
| Sex: Female, Male Male | 92 Participants | 102 Participants | 94 Participants | 288 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 121 / 171 | 124 / 173 | 138 / 171 |
| serious Total, serious adverse events | 26 / 171 | 33 / 173 | 38 / 171 |
Outcome results
Primary
Time to First Bowel Movement
Time to first bowel movement was measured from the end of surgery (defined as the time when the last skin suture or staple was placed in the participant). Time of the first bowel movement was recorded on the electronic case report form (eCRF). The first bowel movement was defined as a normal stool for a postoperative participant based on the clinical judgment of the investigator or designee. Analysis was performed by Kaplan-Meier estimate. Participants who had a bowel movement but were readmitted to the hospital within 1 week after discharge with a diagnosis of postoperative ileus (POI) were considered censored at the time of the first bowel movement as if the bowel movement had not occurred.
Time frame: Day 1 (From the time of end of surgery [that is; from the first dose of study drug administration]) up to Day 10
Population: mITT population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MNTX 12 mg | Time to First Bowel Movement | 4.4 days | Standard Error 0.13 |
| MNTX 24 mg | Time to First Bowel Movement | 4.8 days | Standard Error 0.21 |
| Placebo | Time to First Bowel Movement | 4.6 days | Standard Error 0.15 |
Comparison: Treatment comparisons were made at the overall α=0.05 level (2-sided) using a closed sequential procedure. Placebo and MNTX 24 mg groups were compared first.p-value: 0.4259Log Rank
Comparison: Treatment comparisons were made at the overall α=0.05 level (2-sided) using a closed sequential procedure. Placebo and MNTX 24 mg groups were compared first.p-value: 0.3575Log Rank
Secondary
Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at 0 or 24 Hours as Evaluated by the Opioid-Related Symptom Distress Scale (SDS)
CMEs were defined using opioid-related SDS (assessed participant-reported levels of severity concerning 10 symptoms associated with opioid medication usage: fatigue, drowsiness, inability to concentrate, nausea, dizziness, constipation, itching, difficulty with urination, confusion and retching/vomiting). CME = any symptom rated as severe (3) or very severe (4), with the exception of confusion. A total CME score was calculated by summing the number of CMEs across symptoms and ranged from 0 to 9. CME was counted for either nausea or vomiting/retching, or both and reported in this outcome measure.
Time frame: 0 and 24 hours
Population: mITT population included all randomized participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MNTX 12 mg | Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at 0 or 24 Hours as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | Nausea | 13 Participants |
| MNTX 12 mg | Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at 0 or 24 Hours as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | Vomiting/Retching | 9 Participants |
| MNTX 24 mg | Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at 0 or 24 Hours as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | Nausea | 12 Participants |
| MNTX 24 mg | Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at 0 or 24 Hours as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | Vomiting/Retching | 4 Participants |
| Placebo | Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at 0 or 24 Hours as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | Nausea | 17 Participants |
| Placebo | Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at 0 or 24 Hours as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | Vomiting/Retching | 5 Participants |
Secondary
Time to Discharge Eligibility
Time to discharge eligibility was measured from the end of surgery (defined as the time when the last skin suture or staple was placed in the participant). Discharge eligibility was defined as both tolerance of solid food and at least one bowel movement. Participants were considered to have tolerated solid food when they have eaten greater than or equal to (≥) 50 percent (%), of the first of two successive solid food meals (based on the judgement of the investigator or designee), without vomiting or nausea. Participants readmitted to the hospital with a diagnosis of POI within 7 days of discharge were considered treatment failures. Analysis was performed by Kaplan-Meier estimate.
Time frame: Day 1 (From the time of end of surgery [that is; from the first dose of study drug administration]) up to Day 10
Population: mITT population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MNTX 12 mg | Time to Discharge Eligibility | 5.8 days | Standard Error 0.24 |
| MNTX 24 mg | Time to Discharge Eligibility | 7.0 days | Standard Error 0.45 |
| Placebo | Time to Discharge Eligibility | 6.5 days | Standard Error 0.32 |
Secondary
Time to Discharge Order Written From the End of Surgery
The investigator or designee recorded the time of the order. Participants re-admitted to the hospital with a diagnosis of POI within 7 days after discharge were considered treatment failures. Analysis was performed by Kaplan-Meier estimate.
Time frame: Day 1 (From the time of end of surgery [that is; from the first dose of study drug administration]) up to Day 10
Population: mITT population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MNTX 12 mg | Time to Discharge Order Written From the End of Surgery | 6.8 days | Standard Error 0.26 |
| MNTX 24 mg | Time to Discharge Order Written From the End of Surgery | 9.1 days | Standard Error 0.76 |
| Placebo | Time to Discharge Order Written From the End of Surgery | 7.3 days | Standard Error 0.29 |