Clinical Study to Evaluate the Effectiveness, Safety, and Tolerability of Oxymorphone Immediate Release (IR) Oral Liquid in Post Surgical Pediatric Subjects

Study Overview
=================
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.

Official Title
-----------------
An Open-Label Single-Dose And Randomized, Double-Blind, Placebo-Controlled Multiple-Dose Study To Evaluate The Efficacy, Safety, Tolerability, And Pharmacokinetics Of Oxymorphone Hydrochloride (HCl) For Acute Moderate To Severe Postoperative Pain In Pediatric Subjects

Conditions
-----------------
Post-Operative Pain, Acute Pain

Intervention / Treatment
-----------------
* Drug: Oxymorphone HCl
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Is male or female <2 years of age at the time of surgery. Must weigh at least 3 kg. 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. 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. The subject's parent or guardian has been informed of the nature of the study and has provided written informed consent. Postoperative: 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). Is an inpatient expected to be hospitalized for 24 hours after dosing with study drug. Has an indwelling access catheter for blood sampling. 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. 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: 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. Has any clinical laboratory test result outside the accepted range that has been confirmed upon re-examination and deemed to be clinically significant. Has a clinically significant illness or condition any time before dosing with study drug that would contraindicate participation, as determined by the Investigator. Has a life expectancy <8 weeks. For age groups A and B: Has a malabsorption, gastroenterologic, or abdominal condition that would interfere with the absorption of study drug. Has evidence of increased intracranial pressure. 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%. Has a history of seizures. 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. Subject (and/or mother if subject is nursing) has received preoperative opioids for more than 72 consecutive hours. Subject (and/or mother if subject is nursing) has received oxycodone or oxymorphone within 48 hours prior to screening. 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. 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. Parent or legal guardian is unable to provide consent for any reason (eg, mental or physical disabilities, language barriers, or is unavailable). Subject (and/or mother if subject is nursing) has participated in a clinical study of an unapproved drug within the previous 30 days. Is not suitable for entry into the study in the opinion of the Investigator.

Ages Eligible for Study
-----------------
Minimum Age: 0 Years
Maximum Age: 2 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oxymorphone HCl Open-Label Phase<br>Oxymorphone HCl Immediate Release Oral Liquid and Oxymorphone HCl Injection; open-label, single-dose, dose selection phase. | Drug: Oxymorphone HCl<br>* Oral liquid and injection; dose to be determined by Independent Data Monitoring Committee (IDMC).<br>* Other names: Opana;|
| Experimental: Oxymorphone HCl Multiple-Dose Phase<br>Oxymorphone HCl Immediate Release Oral Liquid and Oxymorphone HCl Injection; placebo controlled, randomized, double-blinded multiple-dose phase. | Drug: Oxymorphone HCl<br>* Oral liquid and injection; dose to be determined by Independent Data Monitoring Committee (IDMC).<br>* Other names: Opana;|
| Placebo Comparator: Placebo<br>Sodium Chloride 0.9% solution; comparator for multiple-dose phase. | Drug: Placebo<br>* Placebo Comparator for the double-blinded, placebo-controlled multiple-dose phase.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Surgical Pain, Acute Post-Surgical Pain