Evaluation of Safety, Pharmacokinetics and Pharmacodynamics of EXPAREL® Administered Via a Single Intrathecal Injection to Healthy Volunteers

Study Overview
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Brief Summary
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Primary objective: To assess the safety and tolerability of EXPAREL® administered as a single intrathecal injection in healthy volunteers Secondary objective: To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of EXPAREL® administered as a single intrathecal injection in healthy volunteers

Detailed Description
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This is a Phase-1, single center, randomized, double-blind, active and placebo-controlled study in approximately 40 healthy adult subjects. On Day 1, eligible subjects will be randomized in blocks of 5, in a ratio of 3:1:1 to receive EXPAREL® or bupivacaine or placebo (saline) injection, respectively. Starting with treatment Cohort 1, healthy volunteers will be randomized to the 3 treatment arms within cohorts. Each cohort will consist of 10 subjects (6 EXPAREL®, 2 bupivacaine and 2 placebo). In each cohort, all 10 subjects in each cohort will receive cerebrospinal fluid (CSF) taps. Within the EXPAREL® arm, subjects will be randomized 2:1 with 4 subjects undergoing CSF tap and 2 subjects not undergoing CSF tap in each cohort. Subjects who are not undergoing CSF tap, will still be injected with needles without draw of CSF to prevent subject bias. Such a randomization will allow for characterization of the complete pharmacodynamics profile of the drug without risk of drug removal in the CSF. For those subjects randomized to the EXPAREL® arm - the dose of EXPAREL® will be determined by the cohort. Starting at 1 mL (13.3 mg) for Cohort 1, the volume of EXPAREL® will be increased by 1 mL in each subsequent cohort for a maximum of 4 mL (53.2 mg). The decision to proceed to the next cohort will be made following a full review of the safety, PK, and PD (sensory and motor) data from current completed cohort(s). All subjects will remain in the EPRU for 5 days after drug administration and will be discharged on Day 6. Subjects will be instructed to return for a follow up visit on Day 9. Adverse events (AEs) and serious adverse events (SAEs) will be recorded from the time of consent through 30 days after drug administration.

Official Title
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Phase 1, Randomized, Double-Blind, Active and Placebo Controlled, Dose Escalation Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of EXPAREL® Administered Via a Single Intrathecal Injection to Healthy Volunteers.

Conditions
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Healthy

Intervention / Treatment
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* Drug: EXPAREL
* Drug: Bupivacaine Hydrochloride
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult male or female volunteers ages ≥18 and ≤50 years old. American Society of Anesthesiologists (ASA) physical status 1. Able to provide informed consent, adhere to the study schedule, and complete all study assessments. Exclusion Criteria: Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications for which an alternative is not named in the protocol (eg, amide-type local anesthetics, opioids, bupivacaine, non-steroidal anti-inflammatory drugs [NSAIDs], spinal anesthesia). Impaired renal or hepatic function (eg, serum creatinine level >2 mg/dL [176.8 μmol/L], blood urea nitrogen level >50 mg/dL [17.9 mmol/L], serum aspartate aminotransferase [AST] level >1.5 times the upper limit of normal [ULN], or serum alanine aminotransferase [ALT] level >1.5 times the ULN). Subjects at an increased risk for bleeding or who have a coagulation disorder (defined as platelet count less than 80,000 × 103/mm3). Concurrent painful physical condition that may require analgesic treatment (such as long-term, consistent use of opioids) in the post dosing period for pain and which may confound the post dosing assessments. Women of childbearing potential must have a documented negative pregnancy test at screening and must be confirmed on the day of drug administration. If postmenopausal, must have a documented Follicle Stimulating Hormone (FSH) test confirming menopause at screening. Currently pregnant, nursing, or planning to become pregnant during the study or within 30 days after completion of the study. Positive serology test result for Human Immunodeficiency Virus (HIV), Hepatitis B virus, or Hepatitis C virus. Clinically significant abnormal ECG that in the opinion of the investigator would preclude the subject from participation in the study. Previous participation in a Pacira study. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past 2 years. 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: The decision to proceed to each next cohort will be made following a full review of the safety, PK, and PD data from the previous completed cohort(s).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EXPAREL®<br>For those subjects randomized to EXPAREL® arm - the dose of EXPAREL® will be determined by the cohort. Starting at 1mL (13.3mg) for cohort 1, the volume of EXPAREL® will be increased by 1 mL in each subsequent cohort for a maximum of 4mL (53.2mg). | Drug: EXPAREL<br>* Injection into the Intrathecal space.<br>|
| Active Comparator: Bupivacaine<br>In each cohort, subjects randomized to the bupivacaine arm will receive 15mg of plain bupivacaine HCL (the equivalent of 13.3mg bupivacaine base) providing a 1:1 reference to the starting dose level chosen for EXPAREL®. | Drug: Bupivacaine Hydrochloride<br>* Injection into the Intrathecal space.<br>* Other names: 0.5% Bupivacaine HCl;|
| Active Comparator: Placebo<br>Subjects in the placebo arm will receive normal saline intrathecal injection | Other: Placebo<br>* Injection into the Intrathecal space.<br>* Other names: Saline;|

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 | Pharmacokinetic endpoint | 6-8 weeks | 
| Maximum plasma concentration (Cmax) and time of Cmax (Tmax). | Pharmacokinetic endpoint | 6-8 weeks | 
| The apparent terminal elimination half-life (t1/2el) | Pharmacokinetic endpoint | 6-8 weeks | 
| Apparent clearance (CL/F) | Pharmacokinetic endpoint | 6-8 weeks | 
| Apparent volume of distribution (Vd) | Pharmacokinetic endpoint | 6-8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent AEs (TEAEs) through Day 9 | Safety endpoint | 6-8 weeks | 
| Proportion of subjects who have any of neurological events | Safety endpoint | 6-8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacodynamics, Pharmacokinetics, Safety, Efficacy