An Open-label Study of Hydromorphone Oral Solution in Subjects Aged 28 Days to 16 Years for Postoperative Pain

Study Overview
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Brief Summary
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The primary objective of this study is to characterize the pharmacokinetics and pharmacodynamics of hydromorphone oral solution in pediatric subjects aged 28 days to 16 years inclusive. The secondary objectives are to characterize the safety and efficacy of hydromorphone oral solution in pediatric subjects aged 28 days to 16 years inclusive.

Detailed Description
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Hydromorphone is an opioid analgesic that has been used for decades as an alternative to morphine in the treatment of moderate to severe malignant and nonmalignant pain. Only a small number of analgesics have been studied in children. The benefits to the subjects include contribution of knowledge that will provide for appropriate dosing regimen recommendations for future pediatric subjects. Treatment consisted of both parenteral and oral hydromorphone. For up to 48 hours immediately following surgery, subjects were administered hydromorphone by IV PCA pump. Dosing with the oral hydromorphone HCl began when the subject was ready to take clear oral liquid. Subjects were administered oral hydromorphone HCl every 6 hours for up to 9 doses. The investigator determined the timing of the first dose based on each subject's clinical condition. The duration of the treatment phase was up to 102 hours (up to 48 hours for the Parenteral Treatment Period and up to 54 hours for the Oral Treatment Period). Efficacy was based on the oral hydromorphone treatment. Adverse events were collected for both the oral and parenteral treatments.

Official Title
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A Multi-center, Open-label, Dose Titration Study Pharmacokinetics/Pharmacodynamics, Safety, and Efficacy of Hydromorphone Oral Solution in Subjects From 28 Days to 16 Years of Age, Who Require Opioid Analgesics for Postoperative Pain

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: Hydromorphone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pediatric subjects aged 28 days to 16 years, Prospective subjects anticipated to have postoperative pain requiring oral opioid analgesics for at least 24 hours (up to 48 hours) following postoperative parenteral analgesia (up to 48 hours), Prospective subjects have received no more than a total of 7 doses of opioids in the 30 days prior to surgery. Exclusion Criteria: Prospective subjects with clinically significant hepatic or renal dysfunction and impaired cardiac and/or respiratory reserve, Prospective subjects who have received opioid analgesic therapy other than hydromorphone or morphine sulfate during the up to 48-hour postoperative period prior to administration of first dose of oral hydromorphone, Prospective subjects who have received regional anesthetic blockade OR analgesic treatment with nonopioid medication within 6 hours prior to administration of first dose of oral hydromorphone. Other protocol-specific inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ≥ 28 Days to < 13 Months<br>infant and toddler | Drug: Hydromorphone<br>* Oral hydromorphone solution dosed every 6 hours up to 9 doses. Dose is determined based on the expected weight range for each age group.<br>* Other names: Adolescent.;|
| Experimental: ≥ 13 months to < 5 years<br>young child | Drug: Hydromorphone<br>* Oral hydromorphone solution dosed every 6 hours up to 9 doses. Dose is determined based on the expected weight range for each age group.<br>* Other names: Adolescent.;|
| Experimental: ≥ 5 years to < 12 years<br>older child | Drug: Hydromorphone<br>* Oral hydromorphone solution dosed every 6 hours up to 9 doses. Dose is determined based on the expected weight range for each age group.<br>* Other names: Adolescent.;|
| Experimental: ≥ 12 years to < 17 years<br>adolescent | Drug: Hydromorphone<br>* Oral hydromorphone solution dosed every 6 hours up to 9 doses. Dose is determined based on the expected weight range for each age group.<br>* Other names: Adolescent.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Population Pharmacokinetic/Pharmacodynamic (PK/PD) Model for Hydromorphone: Clearance (Cl) | Model was built using sparse blood samples: Sampling times: immediately predose, and between 0.25-0.75, 1-3, and 4-6 hours postdose for the first 2 doses of oral hydromorphone: predose for each dose of oral hydromorphone HCl thereafter; and at the end of study. Efficacy was based on Oral treatment only. | A maximum of 9 oral hydromorphone doses with potentially up to 54 hours duration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean (SE) of Faces, Legs Activity, Cry, Consolability (FLACC) Pain Scores on Hydromorphone Alone (Oral/Supplemental) Over Time [Ages >=28 Days to <5 Years] | There are 5 categories in this pediatric pain measurement: face, legs, activity, cry, and consolability. Responses in each category are scored between 0 and 2 (0 = normal, relaxed to 2 = upset, agitated), for a maximum total score of 10. The FLACC scale was used for children under the age of 3 years and older children who have limited verbal skills. | Immediately prior to first oral dose, up to 54 hours | 
| Mean (SE) of Faces Pain Scale-Revised (FPS-R) [Ages >= 5 Years-< 12 Years] Pain Scores on Hydromorphone Alone (Oral/Supplemental)Over Time | Faces Pain Scale-Revised (FPS-R) consists of 6 facial expressions. Each face is 25 x 35 mm with 13 mm between faces. Each subject was asked to point to the face that reflected his or her pain. The end points are 0 = no pain and 10 = very much pain. The FPS-R scale was used for children over the age of 5 up to 12 years who have appropriate verbal skills. | Immediately prior to first oral dose with potentially up to 54 hours duration. | 
| Mean (SE) of Visual Analog Scale (VAS) [Ages 12-16] Pain Scores on Hydromorphone Alone (Oral/Supplemental) Over Time | The Visual Analog Scale (VAS), a 10-cm Color Analog Scale anchored by the descriptors of 0 = no pain and 10 = most pain, was used by children ≥ 12 years of age. | Immediately prior to first oral dose, up to 54 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postoperative pain, Hydromorphone oral solution, opioid, pharmacokinetics, pharmacodynamics