Ileus
Conditions
Keywords
POI, Hernia, Ventral Wall Hernia Repair, Post Operative Ileus
Brief summary
This study will evaluate the safety and efficacy of two different dose regimens (12 milligrams \[mg\] and 24 mg) of IV MOA-728 versus placebo in shortening the time to return of bowel function in participants receiving opioid analgesia administered via patient-controlled anesthesia (PCA), and who had undergone repair of large (greater than or equal to \[≥\]10 centimeters) ventral hernias with or without a mesh prosthesis via laparotomy or laparoscopy.
Interventions
DRUGMOA-728
MOA-728 will be administered per the dose and schedule specified in the arm.
DRUGPlacebo
Placebo matching to MOA-728 will be administered per the schedule specified in the arm.
Sponsors
Progenics Pharmaceuticals, Inc.
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
* Males and females, ages 18 and older. * Scheduled for ventral wall hernia repair with general anesthesia. * Meets the American Society of Anesthesiologists physical status I, II, or III.
Exclusion criteria
* Received investigational drug or procedure within 30 days of randomization. * Women who are pregnant or lactating. * Calculated creatinine clearance (Cockcroft-Gault glomerular filtration rate \[GFR\] formula) less than or equal to (\</=) 50 milliliters/minute (mL/min).
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 tolerance of oral intake of liquids greater than (\>) 500 milliliters (mL) per 8 hours without nausea or retching/vomiting. 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 was considered treatment failures. Analysis was performed by Kaplan-Meier estimate. |
| Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at Day 2 (24 Hours) as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | Day 2 | 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
Australia, Belgium, Canada, Germany, Hungary, Italy, Netherlands, Poland, South Africa, South Korea, United States
Participant flow
Recruitment details
Postoperative participants (who had undergone repair of large \[at least 10 centimeters\] ventral hernias, with or without mesh prosthesis via laparotomy or laparoscopy) were randomized in 1:1:1 ratio to either MOA-728 24 mg, MOA-728 12 mg, or placebo treatment groups.
Pre-assignment details
Participants were prospectively stratified by type of surgery (laparotomy or laparoscopy) and geographic region.
Participants by arm
| Arm | Count |
|---|---|
| MOA-728 12 mg Participants received MOA-728 12 mg as an IV infusion over approximately 20 minutes for approximately every 6 hours for a total of 4 doses in 24-hour period. The first dose of study drug was administered within approximately 90 minutes after completion of the surgical procedure (defined as the time when the last skin suture or staple was placed in the participant). Dose administration was continued for a maximum of 10 days. | 124 |
| MOA-728 24 mg Participants received MOA-728 24 mg as an IV infusion over approximately 20 minutes for approximately every 6 hours for a total of 4 doses in 24-hour period. The first dose of study drug was administered within approximately 90 minutes after completion of the surgical procedure (defined as the time when the last skin suture or staple was placed in the participant). Dose administration was continued for a maximum of 10 days. | 125 |
| Placebo Participants received placebo matched to MOA-728 as an IV infusion over approximately 20 minutes for approximately every 6 hours for a total of 4 doses in 24-hour period. The first dose of study drug was administered within approximately 90 minutes after completion of the surgical procedure (defined as the time when the last skin suture or staple was placed in the participant). Dose administration was continued for a maximum of 10 days. | 124 |
| Total | 373 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 8 | 5 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Other than specified | 2 | 3 | 3 |
| Overall Study | Protocol Violation | 2 | 1 | 4 |
| Overall Study | Randomized but not treated | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 | 5 |
Baseline characteristics
| Characteristic | MOA-728 12 mg | MOA-728 24 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 57.11 years STANDARD_DEVIATION 13.25 | 55.21 years STANDARD_DEVIATION 13.05 | 55.82 years STANDARD_DEVIATION 13.52 | 56.05 years STANDARD_DEVIATION 13.26 |
| Sex: Female, Male Female | 63 Participants | 66 Participants | 68 Participants | 197 Participants |
| Sex: Female, Male Male | 61 Participants | 59 Participants | 56 Participants | 176 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 | 68 / 124 | 71 / 125 | 73 / 124 |
| serious Total, serious adverse events | 20 / 124 | 17 / 125 | 28 / 124 |
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 |
|---|---|---|---|
| MOA-728 12 mg | Time to First Bowel Movement | 93.3 hours | Standard Error 3.2 |
| MOA-728 24 mg | Time to First Bowel Movement | 100.4 hours | Standard Error 4.2 |
| Placebo | Time to First Bowel Movement | 91.3 hours | Standard Error 3.9 |
Comparison: Analysis was performed using log-rank test stratified by surgery type and region for comparisons of survival distributions for active MOA versus Placebo group.p-value: 0.944Log Rank
Comparison: Analysis was performed using log-rank test stratified by surgery type and region for comparisons of survival distributions for active MOA versus Placebo group.p-value: 0.208Log Rank
Secondary
Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at Day 2 (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: Day 2
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 | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MOA-728 12 mg | Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at Day 2 (24 Hours) as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | 10 Participants |
| MOA-728 24 mg | Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at Day 2 (24 Hours) as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | 19 Participants |
| Placebo | Number of Participants With Clinically Meaningful Events (CMEs) for Nausea or Retching/Vomiting at Day 2 (24 Hours) as Evaluated by the Opioid-Related Symptom Distress Scale (SDS) | 7 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 tolerance of oral intake of liquids greater than (\>) 500 milliliters (mL) per 8 hours without nausea or retching/vomiting. 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 |
|---|---|---|---|
| MOA-728 12 mg | Time to Discharge Eligibility | 44.9 hours | Standard Error 2.9 |
| MOA-728 24 mg | Time to Discharge Eligibility | 51.4 hours | Standard Error 5.1 |
| Placebo | Time to Discharge Eligibility | 41.4 hours | Standard Error 3.4 |
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 was 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 |
|---|---|---|---|
| MOA-728 12 mg | Time to Discharge Order Written From the End of Surgery | 130.6 hours | Standard Error 15.52 |
| MOA-728 24 mg | Time to Discharge Order Written From the End of Surgery | 123.8 hours | Standard Error 6.8 |
| Placebo | Time to Discharge Order Written From the End of Surgery | 132.9 hours | Standard Error 14.1 |