PLAY: Multicenter Study for Pediatric Subjects Evaluating Pharmacokinetics and Safety of EXPAREL

• Sponsor: Pacira Pharmaceuticals, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03682302
• Collaborator: (none)
• Enrollment: 98
• Locations: 17
• Arms: 4
• Actual Duration (Months): 5.7
• Patients Per Site: 5.8
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain Management	Drug: Exparel; Drug: 0.5% Bupivacaine HCl	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 98 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Study to Evaluate the Pharmacokinetics and Safety of EXPAREL for Postsurgical Analgesia in Pediatric Subjects Aged 6 to Less Than 17 Years
• Actual Study Start Date: Apr 2, 2019
• Actual Primary Completion Date: Aug 30, 2019
• Actual Study Completion Date: Sep 24, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1: 12 to less than 17 years, undergoing spine surgery, EXPAREL 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; EXPAREL 4mg/kg (maximum 266 mg); Other Names: Liposomal bupivacaine
Active Comparator: Group 1: 12 to less than 17 years, undergoing spine surgery, bupivacine 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; Bupivacaine HCl 2mg/kg; Other Names: Bupivacaine
Experimental: Group 2: 6 to less than 12 years, undergoing spine surgery, EXPAREL 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; EXPAREL 4mg/kg (maximum 266 mg); Other Names: Liposomal bupivacaine
Experimental: Group 2: 6 to less than 12 years, undergoing cardiac surgery, EXPAREL 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; EXPAREL 4mg/kg (maximum 266 mg); Other Names: Liposomal bupivacaine

Outcome Measures

Primary Outcome Measures

1. 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)]

2. 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)]

3. 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)]

4. 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)]

5. 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)]

6. 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)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 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).

2. American Society of Anesthesiologists (ASA) Class 1-3.

3. Male or female subjects 6 to less than 17 years of age on the day of surgery.

4. Body mass index (BMI) at screening within the 5th to 95th percentile for age and sex (see Appendix 5).

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.

6. 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.

7. Subjects must be able to adhere to the study visit schedule and complete all study assessments.

Exclusion Criteria:

1. Currently pregnant, breastfeeding, or planning to become pregnant during the study or within 1 month after study drug administration.

2. History of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics or to opioid medication.

3. Contraindication to bupivacaine HCl or other amide-type local anesthetics or to opioid medication.

4. Administration of EXPAREL or bupivacaine HCl within 30 days prior to study drug administration.

5. Subjects with coagulopathies or immunodeficiency disorders.

6. History of, suspected, or known addiction to or abuse of drugs or alcohol within the past 2 years.

7. Clinically significant medical or psychiatric disease that, in the opinion of the investigator, indicates an increased vulnerability to study drugs and/or procedures.

8. 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:

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University	Loma Linda	California	United States	92354
2	Shriners Hospitals for Children, Northern California	Sacramento	California	United States	95817
3	Stanford University	Stanford	California	United States	94305
4	Children's Hospital Colorado	Aurora	Colorado	United States	80045
5	Nemours / Alfred I. DuPont Hospital for Children	Wilmington	Delaware	United States	19803
6	Nicklaus Children's Hospital	Miami	Florida	United States	33155
7	Shriners Hospitals for Children-Chicago	Chicago	Illinois	United States	60707
8	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana	United States	46204
9	University of Minnesota Masonic Children's Hospital	Minneapolis	Minnesota	United States	55454
10	Duke University Medical Center	Durham	North Carolina	United States	27710
11	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
12	Cleveland Clinic	Cleveland	Ohio	United States	44195
13	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73110
14	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
15	McGovern Medical School at UTHealth	Houston	Texas	United States	77030
16	Southwest Scoliosis Institute	Plano	Texas	United States	75075
17	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Pacira Pharmaceuticals, Inc

Investigators

• Study Director: Igor Grachev, MD, PhD, Pacira Pharmaceuticals, Inc

Study Documents (Full-Text)

• Study Protocol - Oct 1, 2018
• Statistical Analysis Plan - Oct 30, 2019

More Information

Publications

None provided.

• Responsible Party: Pacira Pharmaceuticals, Inc
• ClinicalTrials.gov Identifier: NCT03682302
• Other Study ID Numbers: 402-C-319
• First Posted: Sep 24, 2018
• Last Update Posted: Jan 6, 2021
• Last Verified: Dec 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pacira Pharmaceuticals, Inc: Pediatric
• Additional relevant MeSH terms: Pain, Postoperative; Bupivacaine

Study Results

Participant Flow

Recruitment Details	Participants were recruited between 02 April 2019 and 24 September 2019 at 15 sites in the US (both Groups).

Arm/Group Title	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacine	Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL	Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
Arm/Group Description	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.	Single dose of bupivacaine HCl 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery.	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.	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.
Period Title: Overall Study
STARTED	31	30	6	30
COMPLETED	30	28	5	28
NOT COMPLETED	1	2	1	2

Baseline Characteristics

Arm/Group Title	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacine	Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL	Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL	Total
Arm/Group Description	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.	Single dose of bupivacaine HCl 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery.	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.	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.	Total of all reporting groups
Overall Participants	31	30	5	29	95
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.8 (1.33)	13.9 (1.33)	10 (1.73)	8.7 (1.77)	12.1 (2.81)
Sex: Female, Male (Count of Participants)
Female	28 90.3%	22 73.3%	2 40%	14 48.3%	66 69.5%
Male	3 9.7%	8 26.7%	3 60%	15 51.7%	29 30.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 32.3%	7 23.3%	0 0%	9 31%	26 27.4%
Not Hispanic or Latino	19 61.3%	23 76.7%	5 100%	20 69%	67 70.5%
Unknown or Not Reported	2 6.5%	0 0%	0 0%	0 0%	2 2.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	2 6.5%	0 0%	0 0%	0 0%	2 2.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	1 3.4%	1 1.1%
Black or African American	5 16.1%	3 10%	1 20%	2 6.9%	11 11.6%
White	21 67.7%	26 86.7%	4 80%	26 89.7%	77 81.1%
More than one race	1 3.2%	1 3.3%	0 0%	0 0%	2 2.1%
Unknown or Not Reported	2 6.5%	0 0%	0 0%	0 0%	2 2.1%
Region of Enrollment (participants) [Number]
United States	31 100%	30 100%	5 100%	29 100%	95 100%
American Society of Anesthesiologists classification (Count of Participants)
ASA 1	14 45.2%	13 43.3%	1 20%	0 0%	28 29.5%
ASA 2	16 51.6%	13 43.3%	2 40%	2 6.9%	33 34.7%
ASA 3	1 3.2%	4 13.3%	2 40%	27 93.1%	34 35.8%

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Concentration-versus-time Curve (AUC) 0 to Infinity
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population consisted of subjects who received study drug and provided at least 1 quantifiable plasma concentration, with analysis by actual treatment received.

Arm/Group Title	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacine	Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL	Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
Arm/Group Description	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	Single dose of bupivacaine HCl 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery. 0.5% Bupivacaine HCl: Bupivacaine HCl 2mg/kg	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)
Measure Participants	16	15	2	21
Mean (Standard Deviation) [ng*h/mL]	14246.1 (9118.83)	5709.4 (3281.74)	11569.5 (7306.07)	26164.0 (28038.35)

2. Primary Outcome

Title	Maximum Plasma Concentration (Cmax)
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population consisted of subjects who received study drug and provided at least 1 quantifiable plasma concentration, with analysis by actual treatment received.

Arm/Group Title	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacine	Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL	Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
Arm/Group Description	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	Single dose of bupivacaine HCl 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery. 0.5% Bupivacaine HCl: Bupivacaine HCl 2mg/kg	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)
Measure Participants	16	15	2	21
Mean (Standard Deviation) [ng/mL]	357.3 (125.31)	563.6 (320.93)	319.5 (164.76)	447.1 (243.41)

3. Primary Outcome

Title	The Apparent Terminal Elimination Half-life (t1/2el)
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population consisted of subjects who received study drug and provided at least 1 quantifiable plasma concentration, with analysis by actual treatment received.

Arm/Group Title	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacine	Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL	Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
Arm/Group Description	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	Single dose of bupivacaine HCl 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery. 0.5% Bupivacaine HCl: Bupivacaine HCl 2mg/kg	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)
Measure Participants	16	15	2	21
Mean (Standard Deviation) [hours]	26.8 (21.26)	8.4 (6.26)	13.4 (4.60)	24.9 (20.58)

4. Primary Outcome

Title	Apparent Clearance (CL/F)
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population consisted of subjects who received study drug and provided at least 1 quantifiable plasma concentration, with analysis by actual treatment received.

Arm/Group Title	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacine	Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL	Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
Arm/Group Description	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	Single dose of bupivacaine HCl 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery. 0.5% Bupivacaine HCl: Bupivacaine HCl 2mg/kg	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)
Measure Participants	16	15	2	21
Mean (Standard Deviation) [Liters/hour]	17.5 (7.47)	20.5 (8.27)	14.5 (2.70)	7.4 (3.20)

5. Primary Outcome

Title	Apparent Volume of Distribution (Vd/F)
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population consisted of subjects who received study drug and provided at least 1 quantifiable plasma concentration, with analysis by actual treatment received.

Arm/Group Title	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacine	Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL	Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
Arm/Group Description	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	Single dose of bupivacaine HCl 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery. 0.5% Bupivacaine HCl: Bupivacaine HCl 2mg/kg	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)
Measure Participants	16	15	2	21
Mean (Standard Deviation) [Liters]	546.4 (269.42)	226.8 (110.63)	271.1 (43.58)	216.1 (83.77)

6. Primary Outcome

Title	Area Under the Plasma Concentration-versus-time Curve (AUC) 0 to Tlast
Time Frame	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)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population consisted of subjects who received study drug and provided at least 1 quantifiable plasma concentration, with analysis by actual treatment received.

Arm/Group Title	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacine	Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL	Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
Arm/Group Description	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	Single dose of bupivacaine HCl 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery. 0.5% Bupivacaine HCl: Bupivacaine HCl 2mg/kg	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)	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. Exparel: EXPAREL 4mg/kg (maximum 266 mg)
Measure Participants	16	15	2	21
Mean (Standard Deviation) [ng*h/mL]	9042.5 (3762.82)	5232.9 (2538.37)	10249.6 (5956.56)	16776.4 (7935.80)

Adverse Events

Time Frame	Screening through postsurgical Day 14
Adverse Event Reporting Description	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg, abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov.
Arm/Group Title	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL		Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacaine		Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL		Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
Arm/Group Description	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.		Single dose of bupivacaine HCl 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery.		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.		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.
All Cause Mortality
	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL		Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacaine		Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL		Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/30 (0%)		0/5 (0%)		0/29 (0%)
Serious Adverse Events
	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL		Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacaine		Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL		Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/30 (0%)		0/5 (0%)		2/29 (6.9%)
Gastrointestinal disorders
Vomiting	0/31 (0%)		0/30 (0%)		0/5 (0%)		1/29 (3.4%)
Infections and infestations
Wound infection fungal	0/31 (0%)		0/30 (0%)		0/5 (0%)		1/29 (3.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/31 (0%)		0/30 (0%)		0/5 (0%)		1/29 (3.4%)
Other (Not Including Serious) Adverse Events
	Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, EXPAREL		Group 1: 12 to Less Than 17 Years, Undergoing Spine Surgery, Bupivacaine		Group 2: 6 to Less Than 12 Years, Undergoing Spine Surgery, EXPAREL		Group 2: 6 to Less Than 12 Years, Undergoing Cardiac Surgery, EXPAREL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/31 (61.3%)		22/30 (73.3%)		5/5 (100%)		9/29 (31%)
Cardiac disorders
Tachycardia	1/31 (3.2%)		4/30 (13.3%)		0/5 (0%)		0/29 (0%)
Bradycardia	1/31 (3.2%)		0/30 (0%)		1/5 (20%)		0/29 (0%)
Ear and labyrinth disorders
Hypoacusis	2/31 (6.5%)		1/30 (3.3%)		0/5 (0%)		0/29 (0%)
Eye disorders
Vision blurred	4/31 (12.9%)		3/30 (10%)		3/5 (60%)		1/29 (3.4%)
Visual impairment	2/31 (6.5%)		2/30 (6.7%)		0/5 (0%)		0/29 (0%)
Gastrointestinal disorders
Constipation	8/31 (25.8%)		9/30 (30%)		1/5 (20%)		4/29 (13.8%)
Nausea	10/31 (32.3%)		6/30 (20%)		1/5 (20%)		2/29 (6.9%)
Vomiting	9/31 (29%)		5/30 (16.7%)		1/5 (20%)		4/29 (13.8%)
Hypoesthesia oral	1/31 (3.2%)		3/30 (10%)		3/5 (60%)		0/29 (0%)
Diarrhea	2/31 (6.5%)		0/30 (0%)		1/5 (20%)		0/29 (0%)
Injury, poisoning and procedural complications
Anemia postoperative	4/31 (12.9%)		0/30 (0%)		1/5 (20%)		0/29 (0%)
Delayed recovery from anesthesia	0/31 (0%)		0/30 (0%)		1/5 (20%)		0/29 (0%)
Seroma	0/31 (0%)		0/30 (0%)		1/5 (20%)		0/29 (0%)
Musculoskeletal and connective tissue disorders
Muscle twitching	2/31 (6.5%)		8/30 (26.7%)		1/5 (20%)		1/29 (3.4%)
Muscle spasms	3/31 (9.7%)		0/30 (0%)		1/5 (20%)		0/29 (0%)
Muscular weakness	0/31 (0%)		3/30 (10%)		0/5 (0%)		0/29 (0%)
Nervous system disorders
Dizziness	2/31 (6.5%)		2/30 (6.7%)		0/5 (0%)		0/29 (0%)
Headache	0/31 (0%)		2/30 (6.7%)		0/5 (0%)		0/29 (0%)
Hypoesthesia	0/31 (0%)		2/30 (6.7%)		0/5 (0%)		0/29 (0%)
Paresthesia	0/31 (0%)		2/30 (6.7%)		0/5 (0%)		0/29 (0%)
Renal and urinary disorders
Incontinence	2/31 (6.5%)		0/30 (0%)		0/5 (0%)		0/29 (0%)
Skin and subcutaneous tissue disorders
Pruritis	1/31 (3.2%)		2/30 (6.7%)		2/5 (40%)		0/29 (0%)
Vascular disorders
Hypotension	2/31 (6.5%)		7/30 (23.3%)		2/5 (40%)		0/29 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results conducted at Site shall not be published before 1st multicenter publication by Sponsor but can proceed if there is no such publication ≤18 months after study completion/termination at all sites and all data have been received. Before submitting manuscript/materials to an outside person/entity, site shall give Sponsor 60 days to review and comment. Site shall, upon request, further delay publication/presentation for ≤120 days to allow Sponsor to protect its interests in Inventions.