Multicenter Study for Pediatric Subjects Evaluating Pharmacokinetics and Safety of EXPAREL

Study Overview
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Brief Summary
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Primary Objective: To evaluate the pharmacokinetics (PK) of EXPAREL in pediatric subjects aged 6 to less than 17 years undergoing various types of surgeries. Secondary Objective: To evaluate the safety of EXPAREL in pediatric subjects aged 6 to less than 17 years undergoing various types of surgeries.

Detailed Description
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This is a Phase 3, two-part, multi-center, open-label study designed to evaluate the PK and safety profile of EXPAREL in pediatric subjects aged 6 to less than 17 years when administered intraoperatively at the end of surgery via local infiltration. 90 pediatric subjects undergoing spine and/or cardiac surgeries are planned for enrollment. Part 1 is a multicenter, randomized, open-label study in subjects aged 6 to less than 17 years undergoing spine or cardiac surgeries. There will be 2 treatment groups: Group 1 will include subjects aged 12 to less than 17 years, while Group 2 will include subjects aged 6 to less than 12 years Part 2 is a multicenter, randomized, open-label, safety study in subjects aged 6 to less than 17 years undergoing spine or cardiac surgeries. There will be 2 treatment groups: Group 1 will include subjects aged 12 to less than 17 years, while Group 2 will include subjects aged 6 to less than 12 years. Subjects will be screened within 30 days prior to study drug administration. During the screening visit, subjects will be assessed for past or present neurologic, cardiac, and general medical conditions that, in the opinion of the investigator, would preclude them from study participation. Subjects will undergo their pre-planned spinal or cardiac surgeries per the institution's standard of care. On Day 1, eligible subjects will receive the study drug intraoperatively at the end of surgery via local infiltration into the surgical site. Dosing of EXPAREL will be based on body weight, with a starting dose of 4 mg/kg (maximum 266 mg). There is no required length of stay in the hospital; subjects may be discharged based on the medical judgment of the treating physician. A follow-up phone call will be scheduled for all subjects on Day 7. A final follow-up visit will be made on Day 30 to all subjects who would have received the study drug.

Official Title
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A Multicenter Study to Evaluate the Pharmacokinetics and Safety of EXPAREL for Postsurgical Analgesia in Pediatric Subjects Aged 6 to Less Than 17 Years

Conditions
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Postoperative Pain Management

Intervention / Treatment
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* Drug: Exparel
* Drug: 0.5% Bupivacaine HCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects whose parent(s) or guardian(s) has/have signed and dated the ICF for the subject to participate in the study, and subjects who have provided written assent to participate in the study (if capable). American Society of Anesthesiologists (ASA) Class 1-3. Male or female subjects 6 to less than 17 years of age on the day of surgery. Body mass index (BMI) at screening within the 5th to 95th percentile for age and sex (see Appendix 5). A negative pregnancy test for female subjects of childbearing potential must be available prior to the start of surgery. The pregnancy test must be conducted in the preoperative holding area according to the study site's standard of care. Subjects and their parent(s)/guardian(s) must be able to speak, read, and understand the language of the ICF and any instruments used for collecting subject-reported outcomes to enable accurate and appropriate responses to study assessments, and provide informed consent/assent. Subjects must be able to adhere to the study visit schedule and complete all study assessments. Exclusion Criteria: Currently pregnant, breastfeeding, or planning to become pregnant during the study or within 1 month after study drug administration. History of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics or to opioid medication. Contraindication to bupivacaine HCl or other amide-type local anesthetics or to opioid medication. Administration of EXPAREL or bupivacaine HCl within 30 days prior to study drug administration. Subjects with coagulopathies or immunodeficiency disorders. History of, suspected, or known addiction to or abuse of drugs or alcohol within the past 2 years. Clinically significant medical or psychiatric disease that, in the opinion of the investigator, indicates an increased vulnerability to study drugs and/or procedures. Administration of an investigational drug within 30 days or 5 elimination half-lives of such investigational drug, whichever is longer, prior to study drug administration, or planned administration of another investigational product or procedure during the subject's participation in this study. In addition, the subject will be ineligible to receive study drug if he or she meets the following criterion during surgery: Any clinically significant event or condition uncovered during the surgery (e.g., excessive bleeding, acute sepsis) that might render the subject medically unstable or complicate the subject's postsurgical course.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 12 to less than 17 years, undergoing spine surgery, EXPAREL<br>Single dose of EXPAREL 4 mg/kg (not to exceed a maximum total dose of 266 mg) via local infiltration at the end of spine surgery. | Drug: Exparel<br>* EXPAREL 4mg/kg (maximum 266 mg)<br>* Other names: Liposomal bupivacaine;|
| Active Comparator: Group 1: 12 to less than 17 years, undergoing spine surgery, bupivacine<br>Single dose of bupivacaine hydrochloride (HCl) 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery. | Drug: 0.5% Bupivacaine HCl<br>* Bupivacaine HCl 2mg/kg<br>* Other names: Bupivacaine;|
| Experimental: Group 2: 6 to less than 12 years, undergoing spine surgery, EXPAREL<br>Single dose of EXPAREL 4 mg/kg (not to exceed a maximum total dose of 266 mg) via local infiltration at the end of spine surgery. | Drug: Exparel<br>* EXPAREL 4mg/kg (maximum 266 mg)<br>* Other names: Liposomal bupivacaine;|
| Experimental: Group 2: 6 to less than 12 years, undergoing cardiac surgery, EXPAREL<br>Single dose of EXPAREL 4 mg/kg (not to exceed a maximum total dose of 266 mg) via local infiltration at the end of cardiac surgery. | Drug: Exparel<br>* EXPAREL 4mg/kg (maximum 266 mg)<br>* Other names: Liposomal bupivacaine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-versus-time Curve (AUC) 0 to Infinity |  | 15, 30, 45 min, 1-1.25h, 2-4h, 10-18h, 24-36h, 42-60h (spine surgery) or 15, 30, 45 min, 1-1.25, 15-25, 20-40, 45-55, 64-72h (cardiac surgery) | 
| Maximum Plasma Concentration (Cmax) |  | 15, 30, 45 min, 1-1.25h, 2-4h, 10-18h, 24-36h, 42-60h (spine surgery) or 15, 30, 45 min, 1-1.25, 15-25, 20-40, 45-55, 64-72h (cardiac surgery) | 
| The Apparent Terminal Elimination Half-life (t1/2el) |  | 15, 30, 45 min, 1-1.25h, 2-4h, 10-18h, 24-36h, 42-60h (spine surgery) or 15, 30, 45 min, 1-1.25, 15-25, 20-40, 45-55, 64-72h (cardiac surgery) | 
| Apparent Clearance (CL/F) |  | 15, 30, 45 min, 1-1.25h, 2-4h, 10-18h, 24-36h, 42-60h (spine surgery) or 15, 30, 45 min, 1-1.25, 15-25, 20-40, 45-55, 64-72h (cardiac surgery) | 
| Apparent Volume of Distribution (Vd/F) |  | 15, 30, 45 min, 1-1.25h, 2-4h, 10-18h, 24-36h, 42-60h (spine surgery) or 15, 30, 45 min, 1-1.25, 15-25, 20-40, 45-55, 64-72h (cardiac surgery) | 
| Area Under the Plasma Concentration-versus-time Curve (AUC) 0 to Tlast |  | 15, 30, 45 min, 1-1.25h, 2-4h, 10-18h, 24-36h, 42-60h (spine surgery) or 15, 30, 45 min, 1-1.25, 15-25, 20-40, 45-55, 64-72h (cardiac surgery) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric