Acute Pain, Post-Operative Pain
Conditions
Keywords
Surgical Pain, Acute Post-Surgical Pain
Brief summary
The purpose of the study is to evaluate the efficacy, tolerability, safety and pharmacokinetics of Oxymorphone HCl as an analgesic for acute moderate to severe post-operative pain in pediatric subjects.
Interventions
DRUGOxymorphone HCl
Oral liquid and injection; dose to be determined by Independent Data Monitoring Committee (IDMC).
DRUGPlacebo
Placebo Comparator for the double-blinded, placebo-controlled multiple-dose phase.
Sponsors
Endo Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
0 Years to 2 Years
Healthy volunteers
No
Inclusion criteria
1. Is male or female \<2 years of age at the time of surgery. 2. Must weigh at least 3 kg. 3. Is scheduled to have a surgical procedure for which opioid analgesia will be needed to manage postoperative pain for at least 18 hours following intraoperative and/or postoperative IV analgesia. 4. Is generally healthy as documented by medical history; physical examination (including, but not limited to, the cardiovascular, gastrointestinal, respiratory, and central nervous systems); vital sign assessments; 12-lead electrocardiograms (EKGs); clinical laboratory assessments; and general observations. Any abnormalities or deviations from the acceptable range that might be considered clinically relevant by the study physician or investigator will be evaluated on a case-by-case basis, agreed upon by the Principal Investigator (or sub-investigator), and documented in study files before enrolling the subject in the study. 5. The subject's parent or guardian has been informed of the nature of the study and has provided written informed consent. Postoperative: 6. Is anticipated to require an analgesic regimen using a short-acting opioid (non-oxycodone or non-oxymorphone) analgesic after surgery (according to standard of care (SOC) as defined in the protocol). 7. Is an inpatient expected to be hospitalized for 24 hours after dosing with study drug. 8. Has an indwelling access catheter for blood sampling. 9. For Groups A and B: Has demonstrated signs of tolerating oral intake. All infants and children should be able to demonstrate strong suck and swallow reflexes and neurologic alertness and stability sufficient to handle oral secretions. 10. Prior to administration of oxymorphone HCl oral solution, for Groups A and B, had demonstrated the ability to tolerate clear liquids, following surgery according to the SOC at each institution. All infants and children should be able to demonstrate strong suck and swallow reflexes and neurologic alertness and stability sufficient to handle oral secretions. The ability to tolerate small amounts (1 to 2 oz.) of clear liquids without emesis (over 30 to 60 minutes) would support readiness for study participation and oral intake once the physician has ordered the diet advanced to clear liquids and the subject has ingested fluids by mouth without nausea or vomiting.
Exclusion criteria
Subjects who meet any of the following criteria will not be eligible to participate in the study: 1. Has the presence or history of a clinically significant disorder involving the cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, endocrine, or nervous system(s) or psychiatric disease that would contraindicate participation, as determined by the Investigator. 2. Has any clinical laboratory test result outside the accepted range that has been confirmed upon re-examination and deemed to be clinically significant. 3. Has a clinically significant illness or condition any time before dosing with study drug that would contraindicate participation, as determined by the Investigator. 4. Has a life expectancy \<8 weeks. 5. For age groups A and B: Has a malabsorption, gastroenterologic, or abdominal condition that would interfere with the absorption of study drug. 6. Has evidence of increased intracranial pressure. 7. Has a respiratory condition requiring intubation or resulting in active bronchiolitis, asthma, stridor, or difficulty breathing due to congestion and increased nasal secretions, including oxygen (O2) saturation ≤92%. 8. Has a history of seizures. 9. Subject (and/or mother if subject is nursing) has used medications with actions characteristic of monoamine oxidase inhibitors (MAOIs) within 14 days before the start of the study drug is prohibited. Standard daily pediatric multivitamins may be taken until enrollment into the study but will be restricted during the study. 10. Subject (and/or mother if subject is nursing) has received preoperative opioids for more than 72 consecutive hours. 11. Subject (and/or mother if subject is nursing) has received oxycodone or oxymorphone within 48 hours prior to screening. 12. Subject (and/or mother if subject is nursing) has ingested caffeine- or xanthine-containing products (eg, theophylline) within 48 prior to screening. These products are also prohibited during periods when blood samples are collected. 13. Has a history of relevant drug allergies, food allergies, or both (ie, allergy to oxymorphone or other opioid analgesics) that could interfere with the study. 14. Parent or legal guardian is unable to provide consent for any reason (eg, mental or physical disabilities, language barriers, or is unavailable). 15. Subject (and/or mother if subject is nursing) has participated in a clinical study of an unapproved drug within the previous 30 days. 16. Is not suitable for entry into the study in the opinion of the Investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cumulative Total Amount of Morphine Rescue Medication Required for Analgesia in the Active Treatment Group (Single Dose) | Up to 24 hours post dose |
| Cumulative Total Amount of Morphine Rescue Medication Required for Analgesia in the Active Treatment Group Versus Placebo Group (Multiple Dose). | Up to 24 hours post dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Pain Using the Age Appropriate Scale, Face, Legs, Activity, Cry, Consolability (FLACC) or the Neonatal Infant Pain Scale (NIPS). | Single Dose Phase: at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 8 hours post dose. Multiple Dose Phase: every 0.5 hours up to 24 hours post first dose. | The Face, Legs, Activity, Cry, Consolability (FLACC) was used for patients between the ages of 6 months and 2 years. The FLACC scale is a validated scale that measures pain in patients who are awake or asleep based on a composite score of observations of facial expression, tonicity in legs, activity scores, the presence of crying, and whether the participant is consolable. Each category is scored on a 0 to 2 scale, which results in a total possible score of 0-10. Assessment of the behavioral score are relaxed and comfortable (0), mild discomfort (1-3), moderate pain (4-6), and severe discomfort/pain (7-10). The Neonatal Infant Pain range from 0-7 The NIPS was used for patients 0 to \< 6 months. |
| Pharmacokinetic Variable: Volume of Distribution (Vd) | Single Dose Phase: at 0 (Baseline), 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, and 24 hours post dose. Multiple Dose Phase: Baseline before each dose only | — |
| Pharmacokinetic Variable: Clearance (CL) | Single Dose Phase: at 0 (Baseline), 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, and 24 hours post dose. Multiple Dose Phase: Baseline before each dose | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A (6 Months - <2 Years) 0.05 mg/kg Oxymorphone HCl Immediate Release Oral Liquid and Oxymorphone HCl Injection; open-label, single-dose, dose selection phase. | 6 |
| Group A (6 Months - <2 Years) 0.10 mg/kg Oxymorphone HCl Immediate Release Oral Liquid and Oxymorphone HCl Injection; open-label, single-dose, dose selection phase. | 5 |
| Group A (6 Months - <2 Years) 0.15 mg/kg Oxymorphone HCl Immediate Release Oral Liquid and Oxymorphone HCl Injection; open-label, single-dose, dose selection phase. | 5 |
| Group B (61 Days - <6 Months) 0.10 mg/kg Oxymorphone HCl Immediate Release Oral Liquid and Oxymorphone HCl Injection; open-label, single-dose, dose selection phase. | 5 |
| Oxymorphone HCl Multiple Dose Phase (6 Months - <2 Years) Oxymorphone HCl Immediate Release Oral Liquid and Oxymorphone HCl Injection. | 4 |
| Placebo Sodium Chloride 0.9%; comparator for multiple dose phase. | 3 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Oxymorphone HCl Multiple Dose Phase (6 Months - <2 Years) | Placebo | Total | Group B (61 Days - <6 Months) 0.10 mg/kg | Group A (6 Months - <2 Years) 0.15 mg/kg | Group A (6 Months - <2 Years) 0.10 mg/kg | Group A (6 Months - <2 Years) 0.05 mg/kg |
|---|---|---|---|---|---|---|---|
| Age, Continuous Multiple Dose Safety Population | 396.5 Days STANDARD_DEVIATION 129.88 | 627.0 Days STANDARD_DEVIATION 75.11 | 495.3 Days STANDARD_DEVIATION 159.67 | — | — | — | — |
| Age, Continuous Single Dose Safety Population | — | — | 316.9 Days STANDARD_DEVIATION 159.83 | 108.4 Days STANDARD_DEVIATION 11.72 | 466.4 Days STANDARD_DEVIATION 128.76 | 295.2 Days STANDARD_DEVIATION 84.19 | 384.2 Days STANDARD_DEVIATION 106.83 |
| BMI Multiple Dose Safety Population | 16.83 kg/m^2 STANDARD_DEVIATION 1.841 | 16.73 kg/m^2 STANDARD_DEVIATION 2.775 | 16.79 kg/m^2 STANDARD_DEVIATION 2.065 | — | — | — | — |
| BMI Singe Dose Safety Population | — | — | 17.75 kg/m^2 STANDARD_DEVIATION 1.343 | 17.10 kg/m^2 STANDARD_DEVIATION 1.804 | 18.12 kg/m^2 STANDARD_DEVIATION 1.156 | 18.04 kg/m^2 STANDARD_DEVIATION 0.904 | 17.73 kg/m^2 STANDARD_DEVIATION 1.496 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 11 Participants | 2 Participants | 4 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 2 Participants | 17 Participants | 3 Participants | 1 Participants | 5 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height Multiple Dose Safety Population | 74.25 cm STANDARD_DEVIATION 6.551 | 83.00 cm STANDARD_DEVIATION 1.732 | 78.00 cm STANDARD_DEVIATION 6.658 | — | — | — | — |
| Height Single Dose Safety Population | — | — | 69.80 cm STANDARD_DEVIATION 7.382 | 59.00 cm STANDARD_DEVIATION 3.921 | 74.60 cm STANDARD_DEVIATION 6.387 | 72.28 cm STANDARD_DEVIATION 3.943 | 72.72 cm STANDARD_DEVIATION 2.129 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 5 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 21 Participants | 3 Participants | 4 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 14 Participants | 2 Participants | 3 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 14 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants |
| Weight Multiple Dose Safety Population | 9.33 Kg STANDARD_DEVIATION 1.797 | 11.53 Kg STANDARD_DEVIATION 2.079 | 10.27 Kg STANDARD_DEVIATION 2.109 | — | — | — | — |
| Weight Single Dose Safety Population | — | — | 8.77 Kg STANDARD_DEVIATION 2.031 | 5.95 Kg STANDARD_DEVIATION 0.877 | 10.14 Kg STANDARD_DEVIATION 1.841 | 9.48 Kg STANDARD_DEVIATION 1.442 | 9.39 Kg STANDARD_DEVIATION 0.855 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 4 | 0 / 3 |
| other Total, other adverse events | 4 / 6 | 2 / 5 | 5 / 5 | 2 / 5 | 1 / 4 | 2 / 3 |
| serious Total, serious adverse events | 0 / 6 | 0 / 5 | 1 / 5 | 0 / 5 | 0 / 4 | 0 / 3 |
Outcome results
Primary
Cumulative Total Amount of Morphine Rescue Medication Required for Analgesia in the Active Treatment Group (Single Dose)
Time frame: Up to 24 hours post dose
Population: Single Dose Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (6 Months - <2 Years) 0.05 mg/kg | Cumulative Total Amount of Morphine Rescue Medication Required for Analgesia in the Active Treatment Group (Single Dose) | 3.348 mg | Standard Deviation 3.0745 |
| Group A (6 Months - <2 Years) 0.10 mg/kg | Cumulative Total Amount of Morphine Rescue Medication Required for Analgesia in the Active Treatment Group (Single Dose) | 1.886 mg | Standard Deviation 1.5034 |
| Group A (6 Months - <2 Years) 0.15 mg/kg | Cumulative Total Amount of Morphine Rescue Medication Required for Analgesia in the Active Treatment Group (Single Dose) | 1.400 mg | — |
| Group B (61 Days - <6 Months) 0.10 mg/kg | Cumulative Total Amount of Morphine Rescue Medication Required for Analgesia in the Active Treatment Group (Single Dose) | 0.725 mg | Standard Deviation 0.3797 |
Primary
Cumulative Total Amount of Morphine Rescue Medication Required for Analgesia in the Active Treatment Group Versus Placebo Group (Multiple Dose).
Time frame: Up to 24 hours post dose
Population: Multiple Dose Safety Population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group A (6 Months - <2 Years) 0.10 mg/kg | Cumulative Total Amount of Morphine Rescue Medication Required for Analgesia in the Active Treatment Group Versus Placebo Group (Multiple Dose). | 0.80 mg |
Secondary
Assessment of Pain Using the Age Appropriate Scale, Face, Legs, Activity, Cry, Consolability (FLACC) or the Neonatal Infant Pain Scale (NIPS).
The Face, Legs, Activity, Cry, Consolability (FLACC) was used for patients between the ages of 6 months and 2 years. The FLACC scale is a validated scale that measures pain in patients who are awake or asleep based on a composite score of observations of facial expression, tonicity in legs, activity scores, the presence of crying, and whether the participant is consolable. Each category is scored on a 0 to 2 scale, which results in a total possible score of 0-10. Assessment of the behavioral score are relaxed and comfortable (0), mild discomfort (1-3), moderate pain (4-6), and severe discomfort/pain (7-10). The Neonatal Infant Pain range from 0-7 The NIPS was used for patients 0 to \< 6 months.
Time frame: Single Dose Phase: at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 8 hours post dose. Multiple Dose Phase: every 0.5 hours up to 24 hours post first dose.
Population: Single Dose Phase: Evaluable population =all subjects who received at least 1 dose of drug and provided at least 4 hrs of post-dose assessments and at least 3 PK assessments. Multiple dose Phase: Intent to-treat (ITT) population =all randomized subjects who received at least 1 dose of study drug and completed at least 1 post-dose pain intensity assessment. Due to safety concerns, raised by the IDMC, efficacy analyses were not conducted.
Secondary
Pharmacokinetic Variable: Clearance (CL)
Time frame: Single Dose Phase: at 0 (Baseline), 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, and 24 hours post dose. Multiple Dose Phase: Baseline before each dose
Population: The PK population included all patients who received oxymorphone HCl (immediate-release oral liquid or IV formulation) and had plasma concentration data from at least 1 time point from either single-dose or multiple-dose phase to facilitate the population PK modeling and analysis. The study was terminated early due to safety concerns raised by the IDMC, only the planned safety analyses as specified in the statistical analysis plan were conducted.
Secondary
Pharmacokinetic Variable: Volume of Distribution (Vd)
Time frame: Single Dose Phase: at 0 (Baseline), 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, and 24 hours post dose. Multiple Dose Phase: Baseline before each dose only
Population: The PK (Pharmacokinetic) population included all patients who received oxymorphone HCl (immediate-release oral liquid or IV formulation) and had plasma concentration data from at least 1 time point from either single-dose or multiple-dose phase to facilitate the population PK modeling and analysis. The study was terminated early due to safety concerns raised by the IDMC, only the planned safety analyses as specified in the statistical analysis plan were conducted.