A Phase 1, Open-Label Study to Evaluate the Safety and Pharmacokinetics of Local Administration of EXPAREL When Administered for Prolonged Postsurgical Analgesia in Subjects Undergoing Open Spinal Fusion or Reconstructive Surgery
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Pacira Pharmaceuticals, Inc
- Enrollment
- 15
- Locations
- 3
- Primary Endpoint
- The area under the plasma concentration-versus-time curve from the time of administration extrapolated to infinity. The residual area from the time of the last quantifiable concentration (Ctlast) to infinity is to be calculated using the approximation
Study Overview
Brief Summary
The primary objective of this study is to characterize the pharmacokinetic (PK) profile of EXPAREL when administered via local wound infiltration to subjects undergoing open spinal fusion or reconstructive surgery.
The secondary objectives of this study are to assess the safety, tolerability, and efficacy of EXPAREL in this surgical model.
Detailed Description
This is a Phase 1, multi-center, open-label study designed to evaluate the safety and pharmacokinetics of EXPAREL when administered via local wound infiltration to subjects undergoing open cervical or thoracic spinal fusion or reconstructive surgery.
Fifteen subjects are planned for enrollment. Eligible subjects, whose surgical incision must be at least 8 cm in length, will receive a single dose of EXPAREL (266 mg/20 mL) expanded in volume with 20-60 mL normal saline, depending on the size of the incision. Incision will be performed using a posterior surgical approach.
Administration Technique:
Study drug should be injected in the prescribed locations based on the areas of highest nerve density. Study drug will be administered using syringes with 22-gauge needles prior to wound closure. The Investigator must document the size of the incision. Each infiltration site should be spaced 1.0-1.5 cm apart and should deliver approximately 1-1.5 mL into both deep and superficial areas (para-spinous fascia, muscle, and subcutaneous layers). As each incision will have three layers of infiltration, the total volume to be infiltrated can range from 40-80 mL (please refer to below specifics on how to determine total volume of expansion). Following infiltration, the tissue should visibly expand with minimal leakage.
Total Volume of Expansion:
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Males or females ≥18 years of age.
- •American Society of Anesthesiologists (ASA) physical status 1, 2, or
- •Scheduled to undergo primary, ≥3 level cervical or thoracic spine fusion or reconstruction under general anesthesia. The surgical incision must be at least 8 cm in length.
- •Female subject must be surgically sterile; or at least 2 years postmenopausal; or have a monogamous partner who is surgically sterile; or practicing double-barrier contraception; or practicing abstinence (must agree to use double-barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, or combination oral contraceptive approved by the FDA for greater than 2 months prior to screening and commit to the use of an acceptable form of birth control for the duration of the study and for 30 days after completion of the study.
- •Able to provide informed consent, adhere to the study schedule, and complete all study assessments.
Exclusion Criteria
- •History of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics or opioids.
- •Contraindication to bupivacaine.
- •Received bupivacaine or any other local anesthetic within 7 days of screening.
- •Receiving workers' compensation.
- •Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study drug administration.
- •Non-structural or acute spinal conditions (e.g., cauda equina syndrome, infection, tumor, fracture).
- •Planned concurrent surgical procedure.
- •Comorbidity impacting current physical function or Investigator opinion that it may impact postsurgical rehabilitation.
- •Body weight <50 kg (110 pounds) or a body mass index ≥45 kg/m
- •History of coronary or vascular stent placed within the past 3 months (may be extended to 1 year if medically indicated per physician discretion).
- •Have been treated for a deep vein thrombosis, pulmonary embolism, myocardial infarction, or ischemic stroke within the past 6 months (may be extended to 1 year if medically indicated per physician discretion).
- •Severely impaired renal or hepatic function (e.g., 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 >3 times the upper limit of normal [ULN], or serum alanine aminotransferase [ALT] level > 3 times ULN).
- •Any neurologic or psychiatric disorder that might impact postsurgical pain or interfere with study assessments.
- •Malignancy in the last 2 years, per physician discretion.
- •History of misuse, abuse, or dependence on opioid analgesics, other prescription drugs, illicit drugs, or alcohol.
- •Failure to pass the alcohol breath test or urine drug screen.
- •Current or historical evidence of any clinically significant disease or condition, especially cardiovascular or neurological conditions that, in the opinion of the Investigator, may increase the risk of surgery or complicate the subject's postsurgical course.
- •Clinically significant medical or psychiatric disease that, in the opinion of the Investigator, would constitute a contraindication to participation in the study, or cause inability to comply with the study requirements.
- •Received any investigational drug within 30 days prior to study drug administration, and/or has planned administration of another investigational product or procedure during the subject's participation in this study.
- •Previous participation in an EXPAREL study.
Arms & Interventions
EXPAREL 266 mg/20 mL
Eligible subjects, whose surgical incision must be at least 8 cm in length, will receive a single dose of EXPAREL (266 mg/20 mL) expanded in volume with 20-60 mL normal saline, depending on the size of the incision
Intervention: EXPAREL (Drug)
Outcomes
Primary Outcomes
The area under the plasma concentration-versus-time curve from the time of administration extrapolated to infinity. The residual area from the time of the last quantifiable concentration (Ctlast) to infinity is to be calculated using the approximation
Time Frame: 7 days
The VAS pain intensity scores at each assessed timepoint
Time Frame: 72 hours
Pain intensity scores using the VAS at predose (on Day 1 prior to study drug administration); upon arrival at the post-anesthesia care unit (PACU); at 4, 8, 12, 24, 36, 48, 60, and 72 hours after the beginning of study drug administration; immediately prior to each administration of rescue pain medication; and just prior to hospital discharge
Total inpatient postsurgical opioid consumption (in mg) through 72 hours or hospital discharge
Time Frame: 72 hours
Time to first opioid rescue through 72 hours or hospital discharge
Time Frame: 72 hours
The area under the plasma concentration-versus-time curve from the time of administration to the time of the last quantifiable concentration calculated using the log-linear trapezoidal rule
Time Frame: 7 days
Pharmacokinetic parameters will be estimated from plasma bupivacaine measurements using non-compartmental analysis, based on the sampling schedule at predose (on Day 1 prior to study drug administration); 15 minutes, 30 minutes, 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96 hours after the beginning of study drug administration; and on Day 7
The maximum observed plasma concentration obtained directly from the experimental data without interpolation. Overall, early Cmax (occurring within 2 hours postdose) and late Cmax (occurring after 2 hours postdose) will be presented
Time Frame: 7 days
The time to maximum plasma concentration (Cmax). Overall, early, and late Tmax will be presented
Time Frame: 7 days
The apparent terminal elimination rate constant determined by log-linear regression of the terminal log-linear segment of the plasma concentration-versus-time curve
Time Frame: 7 days
The apparent terminal elimination half-life calculated as 0.693/λz
Time Frame: 7 days
Incidence of TEAEs through Day 30
Time Frame: 30 days
Summary of neurological assessments (proportion of subjects who are oriented and proportion of subjects who have any of the neurological events
Time Frame: 30 days
Change from baseline in ECG data closest to the median Tmax
Time Frame: 30 days
Investigator assessment of the ECG (normal, abnormal - not clinically significant, abnormal - clinically significant)
Time Frame: 30 days
Change from baseline in vital signs at each assessed timepoint
Time Frame: 30 days
Secondary Outcomes
No secondary outcomes reported