Clinical Trial Results:
A Phase 1, Open-Label Study to Evaluate the Pharmacokinetics and Safety of Local Administration of EXPAREL for Postsurgical Analgesia in Pediatric Subjects 12 to Less Than 17 Years of Age
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Summary
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EudraCT number |
2023-000584-31 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
12 Feb 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Aug 2023
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First version publication date |
17 Aug 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
402-C-120
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03485014 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Pacira Pharmaceuticals, Inc.
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Sponsor organisation address |
5 Sylvan Way, Parsippany/NJ, United States, 07054
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Public contact |
Medical Information, Pacira Pharmaceuticals, Inc., medinfo@pacira.com
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Scientific contact |
Medical Information, Pacira Pharmaceuticals, Inc., medinfo@pacira.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000877-PIP03-17 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Feb 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Feb 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to evaluate the pharmacokinetics of EXPAREL in pediatric subjects 12 to less than 17 years of age undergoing spinal surgery.
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Protection of trial subjects |
The study was conducted in accordance with the clinical research guidelines established by the Food and Drug Administration (FDA) Title 21 Code of Federal Regulation (CFR), Parts 50 (including Subpart D regarding additional safeguards for children in clinical investigations), 54, 56, and 312. Any other requirements necessary for the protection of the human rights of the subject were also explained according to the current International Council for Harmonisation-Good Clinical Practice (ICH-GCP) guideline and the Declaration of Helsinki. Subjects were allowed to be treated with prophylactic antibiotics according to surgeon´s preference, and with intraoperative opioids (other than ultra short-acting opioids [e.g., fentanyl, sufentanil, or remifentanil]), acetaminophen, ketorolac, or other nonsteroidal anti-inflammatory drugs in accordance with the study site´s standard of care.
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Background therapy |
There were restrictions on the use of concomitant medications/therapies during the trial/surgery. The following medications/therapies were not permitted: use of an investigational drug within 30 days or 5 elimination half-lives of such investigational drug prior to study drug administration, or planned administration of another investigational product or procedure during the subject´s participation in the study. In addition, no drugs were to be admixed with study drug (e.g., epinephrine, dexamethasone, clonidine). Lidocaine and other local anesthetics were not permitted intraoperatively. | ||
Evidence for comparator |
This was a single treatment group where all eligible subjects were treated with the study drug: EXPAREL | ||
Actual start date of recruitment |
10 Apr 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 15
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Worldwide total number of subjects |
15
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
15
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
15 subjects (12 to less than 17 years of age) were screened for eligibility in 1 trial site in the United States. All received the study drug and completed the study. No screening failures were reported. | ||||||
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Pre-assignment
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Screening details |
15 male or female subjects, from 12 to less than 17 years of age on the day of surgery who had an American Society of Anesthesiologists Class of 1 to 3 were screened. | ||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
This was an open-label study where all eligible subjects were administered with EXPAREL
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Arms
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Arm title
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EXPAREL | ||||||
Arm description |
Eligible subjects received a single dose of EXPAREL (4 mg/kg) intraoperatively at the end of surgery via local infiltration into the surgical site. EXPARELwas administered prior to wound closure. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
EXPAREL
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Injection
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Dosage and administration details |
Single dose of EXPAREL (4 mg/kg) intraoperatively administered at the end of surgery via local infiltration into the surgical site. EXPAREL was administered prior to wound closure
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial (overall period)
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Reporting group description |
Subjects receiving single injectable suspension of EXPAREL 4 mg/kg on Day 1 at the end of surgery into the surgical site. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
EXPAREL
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Reporting group description |
Eligible subjects received a single dose of EXPAREL (4 mg/kg) intraoperatively at the end of surgery via local infiltration into the surgical site. EXPARELwas administered prior to wound closure. | ||
Subject analysis set title |
Safety analysis set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety analysis set consisted of all subjects who underwent the planned surgery and received study drug
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Subject analysis set title |
Pharmacokinetics analysis set
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The pharmacokinetic analysis set included all subjects who received study drug and provided at least 1 quantifiable plasma concentration
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End point title |
AUC [1] | ||||||||
End point description |
Area under the plasma concentration-versus-time-curve
Per original protocol and protocol amendment 1, 5 blood samples were collected from each subject during scheduled time windows:
Group 1: blood samples were taken approximately 30 minutes, 190 minutes, 17.5 hours, 42.5 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
Group 2: blood samples were taken approximately 30 minutes, 210 minutes, 22.5 hours, 47.5 hours, and 72 to 96 hours after EXPAREL administration (3 subjects)
Group 3: blood samples were taken approximately 30 minutes, 230 minutes, 27.5 hours, 53 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
The population PK model estimated EXPAREL individual and population PK parameters and exposure, inter-individual variability of PK parameters, and intra-individual variability of bupivacaine concentrations following a predicted model.
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End point type |
Primary
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End point timeframe |
Protocol Amendment 2: Eight blood samples were collected per subject as specific time windows (15 minutes, 30 minutes, 45 minutes, 1 to 1.25 hours, 2 to 3 hours, 10 to 18 hours, 24 to 36 hours, and 42 to 60 hours after EXPAREL administration) - 8 subjects
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Nonlinear mixed-effect modelling was used to analyse the sparse concentration-versus-time data. Because of different sampling times across sampling groups and small sample size for each sampling group, no non-compartmental PK parameters were derived and no summary was performed for the PK concentration by time point. The study was single arm and no statistical analyses were performed for this endpoint |
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End point title |
Early Cmax [2] | ||||||||
End point description |
Early maximum plasma concentration
Per original protocol and protocol amendment 1, 5 blood samples were collected from each subject during scheduled time windows:
Group 1: blood samples were taken approximately 30 minutes, 190 minutes, 17.5 hours, 42.5 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
Group 2: blood samples were taken approximately 30 minutes, 210 minutes, 22.5 hours, 47.5 hours, and 72 to 96 hours after EXPAREL administration (3 subjects)
Group 3: blood samples were taken approximately 30 minutes, 230 minutes, 27.5 hours, 53 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
The population PK model estimated EXPAREL individual and population PK parameters and exposure, inter-individual variability of PK parameters, and intra-individual variability of bupivacaine concentrations following a predicted model.
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End point type |
Primary
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End point timeframe |
Protocol Amendment 2: Eight blood samples were collected per subject as specific time windows (15 minutes, 30 minutes, 45 minutes, 1 to 1.25 hours, 2 to 3 hours, 10 to 18 hours, 24 to 36 hours, and 42 to 60 hours after EXPAREL administration) - 8 subjects
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Nonlinear mixed-effect modelling was used to analyse the sparse concentration-versus-time data. Because of different sampling times across sampling groups and small sample size for each sampling group, no non-compartmental PK parameters were derived and no summary was performed for the PK concentration by time point. The study was single arm and no statistical analyses were performed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Late Cmax [3] | ||||||||
End point description |
Late maximum plasma concentration
Per original protocol and protocol amendment 1, 5 blood samples were collected from each subject during scheduled time windows:
Group 1: blood samples were taken approximately 30 minutes, 190 minutes, 17.5 hours, 42.5 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
Group 2: blood samples were taken approximately 30 minutes, 210 minutes, 22.5 hours, 47.5 hours, and 72 to 96 hours after EXPAREL administration (3 subjects)
Group 3: blood samples were taken approximately 30 minutes, 230 minutes, 27.5 hours, 53 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
The population PK model estimated EXPAREL individual and population PK parameters and exposure, inter-individual variability of PK parameters, and intra-individual variability of bupivacaine concentrations following a predicted model.
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End point type |
Primary
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End point timeframe |
Protocol Amendment 2: Eight blood samples were collected per subject as specific time windows (15 minutes, 30 minutes, 45 minutes, 1 to 1.25 hours, 2 to 3 hours, 10 to 18 hours, 24 to 36 hours, and 42 to 60 hours after EXPAREL administration) - 8 subject
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Nonlinear mixed-effect modelling was used to analyse the sparse concentration-versus-time data. Because of different sampling times across sampling groups and small sample size for each sampling group, no non-compartmental PK parameters were derived and no summary was performed for the PK concentration by time point. The study was single arm and no statistical analyses were performed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
T1/2el [4] | ||||||||
End point description |
The apparent terminal elimination half-life
Per original protocol and protocol amendment 1, 5 blood samples were collected from each subject during scheduled time windows:
Group 1: blood samples were taken approximately 30 minutes, 190 minutes, 17.5 hours, 42.5 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
Group 2: blood samples were taken approximately 30 minutes, 210 minutes, 22.5 hours, 47.5 hours, and 72 to 96 hours after EXPAREL administration (3 subjects)
Group 3: blood samples were taken approximately 30 minutes, 230 minutes, 27.5 hours, 53 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
The population PK model estimated EXPAREL individual and population PK parameters and exposure, inter-individual variability of PK parameters, and intra-individual variability of bupivacaine concentrations following a predicted model.
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End point type |
Primary
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End point timeframe |
Protocol Amendment 2: Eight blood samples were collected per subject as specific time windows (15 minutes, 30 minutes, 45 minutes, 1 to 1.25 hours, 2 to 3 hours, 10 to 18 hours, 24 to 36 hours, and 42 to 60 hours after EXPAREL administration) - 8 subjects
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Nonlinear mixed-effect modelling was used to analyse the sparse concentration-versus-time data. Because of different sampling times across sampling groups and small sample size for each sampling group, no non-compartmental PK parameters were derived and no summary was performed for the PK concentration by time point. The study was single arm and no statistical analyses were performed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
CL/F [5] | ||||||||
End point description |
Apparent clearance
Per original protocol and protocol amendment 1, 5 blood samples were collected from each subject during scheduled time windows:
Group 1: blood samples were taken approximately 30 minutes, 190 minutes, 17.5 hours, 42.5 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
Group 2: blood samples were taken approximately 30 minutes, 210 minutes, 22.5 hours, 47.5 hours, and 72 to 96 hours after EXPAREL administration (3 subjects)
Group 3: blood samples were taken approximately 30 minutes, 230 minutes, 27.5 hours, 53 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
The population PK model estimated EXPAREL individual and population PK parameters and exposure, inter-individual variability of PK parameters, and intra-individual variability of bupivacaine concentrations following a predicted model.
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End point type |
Primary
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End point timeframe |
Protocol Amendment 2: Eight blood samples were collected per subject as specific time windows (15 minutes, 30 minutes, 45 minutes, 1 to 1.25 hours, 2 to 3 hours, 10 to 18 hours, 24 to 36 hours, and 42 to 60 hours after EXPAREL administration) - 8 subjects
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Nonlinear mixed-effect modelling was used to analyse the sparse concentration-versus-time data. Because of different sampling times across sampling groups and small sample size for each sampling group, no non-compartmental PK parameters were derived and no summary was performed for the PK concentration by time point. The study was single arm and no statistical analyses were performed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Vss [6] | ||||||||
End point description |
Apparent volume of distribution at steady-state
Per original protocol and protocol amendment 1, 5 blood samples were collected from each subject during scheduled time windows:
Group 1: blood samples were taken approximately 30 minutes, 190 minutes, 17.5 hours, 42.5 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
Group 2: blood samples were taken approximately 30 minutes, 210 minutes, 22.5 hours, 47.5 hours, and 72 to 96 hours after EXPAREL administration (3 subjects)
Group 3: blood samples were taken approximately 30 minutes, 230 minutes, 27.5 hours, 53 hours, and 72 to 96 hours after EXPAREL administration (2 subjects)
The population PK model estimated EXPAREL individual and population PK parameters and exposure, inter-individual variability of PK parameters, and intra-individual variability of bupivacaine concentrations following a predicted model.
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End point type |
Primary
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End point timeframe |
Protocol Amendment 2: Eight blood samples were collected per subject as specific time windows (15 minutes, 30 minutes, 45 minutes, 1 to 1.25 hours, 2 to 3 hours, 10 to 18 hours, 24 to 36 hours, and 42 to 60 hours after EXPAREL administration) - 8 subject
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Nonlinear mixed-effect modelling was used to analyse the sparse concentration-versus-time data. Because of different sampling times across sampling groups and small sample size for each sampling group, no non-compartmental PK parameters were derived and no summary was performed for the PK concentration by time point. The study was single arm and no statistical analyses were performed for this endpoint |
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Adverse events information
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Timeframe for reporting adverse events |
From the time the informed consent form (ICF) was signed/assent was obtained through end of the study (Day 30)
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Adverse event reporting additional description |
Subjects were expected to volunteer information about adverse events that they experienced. In addition, the investigator or designee questioned the subject at each visit about adverse events and recorded these as well as other adverse events at the visit.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
EXPAREL
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Reporting group description |
Eligible subjects received a single dose of Exparel (4 mg/kg) intraoperatively at the end of surgery via local infiltration into the surgical site. Exparel was administered prior to wound closure. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 Jan 2018 |
The clinically relevant changes made under this protocol amendment are summarized below:
- Specified that the baseline 12-lead electrocardiogram (ECG) may have been performed either at the screening visit or in the preoperative holding area on Day 1 prior to surgery
- Added that a pregnancy test for female subjects of childbearing potential was to be conducted in the preoperative holding area according to the site´s study of care and a negative result for the pregnancy test must have been available prior to the start of surgery.
- Removed local anesthetics (other than study drug) from the list of permitted intraoperative medications
- Specified that a follow-up call was to occur on Day 7 and a follow-up physical examination, including examination of the surgical site, was to occur on Day 30.
- Added that date and time of admission to the hospital were to be recorded on the day of surgery (Day 1)
- Removed urine drug screen and blood alcohol test from screening procedures.
Note: A total of 7 subjects of the 15 included were enrolled under amendment 1. |
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24 Sep 2018 |
The clinically relevant changes made under this protocol amendment are summarized below:
- Added that the maximum single dose of EXPAREL in this study was to be 266 mg.
- Changed the total number of pharmacokinetic (PK) samples from 5 to 8 and adjusted PK sample times and collection windows; PK blood draws were changes from starting at 30 minutes after the end of study drug administration and continuing at various timepoints through 96 hours to starting at 15 minutes after the end of study drug administration and continuing at various timepoints through 60 hours; removed different PK sampling groups, and therefore, also removed the need to randomize subjects to these PK sampling groups (Note: Footnote 7 of Protocol Table 1 specified measuring PK assessment from the start of study drug administration, and this instruction was followed by the investigator).
- Added text describing the initial approval (2011) and amended indication approval (2018) of EXPAREL by the Food and Drug Administration (FDA).
Note: A total of 8 subjects of the 15 included were enrolled under amendment 2
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
