Phase 4 Study in Adult Subjects Undergoing Posterior Lumbar Spine Surgeries

A Multicenter, Prospective, Active Controlled, Real World, Phase 4 Study of EXPAREL in Multimodal Regimens Compared With Standard of Care for Postsurgical Pain Management in Subjects Undergoing Lumbar Posterior Spine Surgeries (FUSION)

Primary Objective: The primary objective of this study is to compare postsurgical opioid consumption through 72 hours postsurgery in patients receiving local infiltration analgesia (LIA) with EXPAREL and bupivacaine HCl (EXPAREL group) with that of patients receiving standard of care (SOC) (control group) in adult subjects undergoing posterior lumbar spine surgeries where both groups are receiving a multimodal pain regimen.

Secondary Objectives: The secondary objectives of this study are to:

1. Compare safety and effectiveness outcomes following LIA with EXPAREL and bupivacaine hydrochloride (HCl) versus SOC in adult subjects undergoing posterior lumbar spine surgeries through 72 hours, including time to first opioid and opioid-related adverse events (ORAEs).
2. Compare health outcomes following LIA with EXPAREL and bupivacaine hydrochloride (HCl) versus SOC in adult subjects undergoing posterior lumbar spine surgeries, including discharge readiness, hospital (or other facility) length of stay (LOS), discharge disposition, hospital readmissions, and health service utilization.

This is a Phase 4, multicenter, prospective, active-controlled, real world, study in approximately 225 adult subjects undergoing posterior lumbar spine surgery under general anesthesia.

Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be allowed but is discouraged. If a subject can only be screened on the day of surgery, the informed consent process must still be started at least 24 hours prior to the conduct of any screening procedures that are not considered SOC at the institution and such procedures may not be performed until written informed consent is provided. All screening procedures that are not SOC must be performed and documented within the 30-day time window (inclusive of the day of surgery for those subjects who can only be screened on the day of surgery) as described here.

During the screening visit, subjects will be assessed for any past or present medical conditions that in the opinion of the investigator would preclude them from study participation. After the ICF is signed, the following information will be recorded and procedures done: medical history, surgical history, medication history, the subject's opioid use history will be recorded to calculate mean daily mg oral morphine equivalent dosing (MED PO) in the last 30 days, demographic and background information, height, weight and body mass index (BMI), a urine pregnancy test for women of childbearing potential, and the subject's current adverse experiences (AEs), if any.

Subjects will be asked questions and/or be asked to fill forms as part of the following assessments: Brief Pain Inventory - short form (BPI-sf), 5-item Opioid Compliance Checklist (OCC), Hospital Anxiety and Depression Scale (HADS), Survey of Pain Attitudes (SOPA), Numeric Rating Scale (NRS) ti assess pain and Opioid Related Symptom Distress Scale (ORSDS).

Based on the planned surgical procedure, subjects will be placed in one of three cohorts:

• Cohort 1 - Open lumbar spinal fusion technique; ("open" cohort)
• Cohort 2 - Minimally invasive tubular and/or percutaneous pedicle screw insertion for lumbar decompression with or without fusion;("tubular/percutaneous without midline incision" cohort)
• Cohort 3 - Lumbar decompression surgery (LDS) without fusion (discectomy or laminectomy outpatient cohort)

The initial sample size in each study cohort (i.e., cohort 1, cohort 2 and cohort 3) is estimated at 75 subjects (50 subjects with EXPAREL and 25 subjects with Control group), for a total of 225 subjects in all three cohorts. Within each assigned cohort, subjects will be allocated in a 2:1 ratio to the EXPAREL (50 subjects) and Control group (25 subjects).

The following sequence will be followed for all cohorts: First, the subjects who meet eligibility criteria will be treated according to the institution's SOC. Their data will be collected prospectively. Next, at each investigational site, the administration of EXPAREL and bupivacaine HCl to the first 1 to 3 subjects in each cohort will be observed to ensure that the correct procedure for infiltration as described in the infiltration guide is being followed. If the infiltration was performed correctly, the subject will be included in the study. If the infiltration was performed incorrectly, the subject will continue in the study but will be removed from statistical analysis and will be replaced to ensure at least 50 evaluable EXPAREL patients are enrolled per cohort. If subjects are discontinued for other reasons, they will be replaced such that a total sample size of 75 fully evaluable subjects is obtained in each study cohort, with 50 in the EXPAREL group and 25 in the Control group.

Inclusion Criteria:

1. 18-75 years old at the time of screening.

2. Primary surgical indication is related to spinal degenerative disease, including any of the following:

   1. Spinal stenosis
   2. Spondylolisthesis
   3. Radiculopathy/instability disc disorders
   4. Degenerative disc disease

3. Medically cleared for elective spine surgery.

4. Scheduled to undergo:

   1. Elective (i.e., not emergency)
   2. Lumbosacral (i.e., L1-S1)
   3. Posterior approach with posterior instrumentation

5. Cohort 1 - Open only:

   Open or mini-open surgical technique with:

   1. 1-level (i.e., spanning 2 vertebrae) or 2-level (i.e., spanning 3 contiguous vertebrae)
   2. Primary fusion or revision fusion
   3. Open or mini-open surgical technique

6. Cohort 2 - Tubular or percutaneous cohort only:

   1. 1-level (i.e., spanning 2 vertebrae) or 2-level (i.e., spanning 3 contiguous vertebrae)
   2. Primary fusion or revision fusion
   3. Tubular or percutaneous surgical technique

7. Cohort 3 - Lumbar decompression without fusion outpatient cohort only:

   1. Radiculopathy
   2. Spinal stenosis

8. Able to provide informed consent and adhere to all study assessments and visit schedule

Exclusion Criteria:

1. Serious spinal pathology determined by Investigator that might meaningfully affect postsurgical outcomes, including any of the following:

   1. Suspected cauda equina syndrome (e.g., bowel/bladder involvement)
   2. Infection
   3. Tumor
   4. Fracture
   5. Systemic inflammatory spondyloarthropathy

2. Contraindication to local anesthesia according to the clinical judgment of the Investigator and based on the EXPAREL label.

3. Patients who most likely will require patient-controlled analgesia (PCA) pumps in EXPAREL group.

4. Anterior surgical approaches, including any of the following:

   1. Anterior lumbar interbody fusion (ALIF)
   2. Oblique lumbar interbody fusion (OLIF)
   3. Anterior-posterior or 360º fusion

5. Lateral surgical approaches, including any of the following:

   1. Extreme lateral interbody fusion (XLIF)
   2. Direct lateral interbody fusion (DLIF)

6. High-dose presurgical opioid use:

   a) Mean daily intake greater than 100 mg mEq PO in the past 30 days

7. Known allergy, hypersensitivity, or contraindication to any of the following study medications:

   1. Bupivacaine
   2. EXPAREL
   3. Tylenol (acetaminophen)
   4. Robaxin
   5. 2 or more NSAIDs
   6. 2 or more gabapentinoids
   7. 2 or more rescue opioids (e.g., oxycodone, morphine, hydromorphone)
   8. 2 or more medications for postoperative nausea, vomiting, or pruritus (e.g., dexamethasone, ondansetron)

8. History of severely impaired renal or hepatic function.

9. Severe chronic pain that requires analgesic treatment, and in the opinion of the principal Investigator, is likely to meaningfully affect postsurgical outcomes.

10. Subjects that have implanted spinal cord stimulator or intrathecal drug pump.

11. Any neurologic or psychiatric disorder that might impact postsurgical pain or interfere with study assessments per Investigator discretion.

12. Malignancy in the last 2 years.

13. History of misuse, abuse, or dependence on opioid analgesics, other prescription drugs, illicit drugs, or alcohol as defined in DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). Dependence or chronic opioid use will be defined as use of more than 30 morphine equivalents per day during the prior 90 days.

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

15. Body Mass Index < 17 kg/m2 or >44 kg/m2 at screening

16. Subjects receiving Worker's Compensation for disability or who are involved in other litigation related to the spine.

17. Planned concurrent surgical procedure.

18. Previous participation in an EXPAREL study.

19. Administration of any 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 might be excluded from the study prior to study drug infiltration if one of the following criteria during the surgical procedure is met:

1. Unable to place planned surgical instrumentation
2. Poor fixation at the time of surgical instrumentation

In addition, the subject must be considered an early termination if one of the following criteria after the surgical procedure is met:

1. An incision size >20 cm

2. Autograft taken from a harvest site other than surgical site (i.e., iliac crest autograft)

3. Intraoperative complications likely to meaningfully affect postsurgical outcomes, including any of the following:

   1. Clinically significant and prolonged (i.e., >24 hours) neurologic deficit (e.g., foot drop)
   2. Dural tear or suspected dural tear requiring bed rest (exception: subject will be allowed if the dural tear is fixed as per SOC of the institution during surgery)
   3. Extensive bleeding (i.e., >1,000 mL blood loss)
   4. Symptomatic epidural hematoma