Efficacy, Safety, and Pharmacokinetics of Femoral Nerve Block With EXPAREL in Total Knee Arthroplasty

• Sponsor: Pacira Pharmaceuticals, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02713178
• Collaborator: (none)
• Enrollment: 232
• Locations: 17
• Arms: 3
• Duration (Months): 12.9
• Patients Per Site: 13.6
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in 232 adult subjects undergoing primary unilateral TKA under general or spinal anesthesia.

Condition or Disease	Intervention/Treatment	Phase
Pain	Drug: bupivacaine liposome injectable suspension; Drug: Placebo	Phase 3

Detailed Description

On Day 0, eligible subjects will be randomized in a 1:1:1 ratio to receive a single dose of either EXPAREL 133 mg in 10 mL expanded in volume with 10 mL of normal saline for a total volume of 20 mL (Group 1); EXPAREL 266 mg in 20 mL (Group 2); or placebo 20 mL (Group 3). Study drug (EXPAREL or placebo) will be administered in a blinded manner via an ultrasound guided single-dose femoral nerve block at least 1 hour prior to surgery. Prior to placement of the prosthesis, 8 mL of bupivacaine hydrochloride (HCl) (0.5%) diluted with 8 mL of normal saline will be administered by the surgeon as a periarticular infiltration to the posterior capsule (8 mL medially and 8 mL laterally).

Postsurgical assessments will include pain intensity scores using a 10-cm visual analog scale (VAS); total postsurgical opioid consumption; overall benefit of analgesia score (OBAS) questionnaire; subject satisfaction with overall analgesia using a 5-point Likert scale; neurological assessment; sensory function assessment; motor function assessment; the study physical therapy assessments (ie, timed walk, timed up and go, and stair climbing tests); discharge readiness; unscheduled phone calls or office visits related to pain; 12-lead ECGs; vital sign measurements; and clinical laboratory tests. Adverse events will be recorded from the time the informed consent form (ICF) is signed through postsurgical Day 29.

Follow-up visits will be scheduled for all subjects on postsurgical Days 6 and 10. A follow-up phone call will be made on postsurgical Day 29.

Pharmacokinetic (PK) parameters will be estimated from plasma bupivacaine measurements using non-compartmental analysis based on the sampling schedule of baseline (prior to the nerve block) through postsurgical Day 10.

Study Design

• Study Type: Interventional
• Actual Enrollment: 232 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of Femoral Nerve Block With EXPAREL for Postsurgical Analgesia in Subjects Undergoing Total Knee Arthroplasty
• Study Start Date: Jun 3, 2016
• Actual Primary Completion Date: Jun 30, 2017
• Actual Study Completion Date: Jun 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: EXPAREL 133 mg Single dose of 133 mg (10 mL) EXPAREL (bupivacaine liposome injectable suspension) expanded in volume with 10 mL of normal saline for a total volume of 20 mL.	Drug: bupivacaine liposome injectable suspension; bupivacaine liposome injectable suspension 133 mg expanded with normal saline to 20 mL or 266 mg in 20 mL; Other Names: EXPAREL
Active Comparator: EXPAREL 266 mg Single dose of 266 mg (20 mL) EXPAREL (bupivacaine liposome injectable suspension).	Drug: bupivacaine liposome injectable suspension; bupivacaine liposome injectable suspension 133 mg expanded with normal saline to 20 mL or 266 mg in 20 mL; Other Names: EXPAREL
Placebo Comparator: Placebo Normal saline (20 mL).	Drug: Placebo; Normal saline.; Other Names: Normal saline

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores Through 72 Hours [0-72 hours]

   AUC of VAS pain intensity scores through 72 hours. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, "How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now."

Secondary Outcome Measures

1. Total Postsurgical Opioid Consumption Through 72 Hours [0-72 hours]

   Total postsurgical opioid consumption (converted to IV morphine equivalents) through 72 hours

2. Percentage of Opioid-free Participants Through 72 Hours [0-72 hours]

   Percentage of participants who did not receive opioid medication through 72 hours

3. Time to First Opioid Rescue Through 72 Hours [0-72 hours]

   Time to first opioid rescue medication consumed through 72 hours. The "time to rescue" is estimated for each quartile from the Kaplan-Meier analysis, in which first quartile represents the time it took for the first 25% of the population to receive rescue medication, median quartile represents the time it took 50% of the population to receive rescue medication, and third quartile represents the time it took 75% of the population to receive rescue medication.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female, at least 18 years of age at screening.

2. Scheduled to undergo primary unilateral TKA under general or spinal anesthesia.

3. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3.

4. 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.

5. Able to demonstrate sensory function by exhibiting sensitivity to cold, pinprick, and light touch.

6. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments.

Exclusion Criteria:

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

2. Planned concurrent surgical procedure (e.g., bilateral TKA).

3. Concurrent painful physical condition that may require analgesic treatment (such as an NSAID or opioid) in the postsurgical period for pain that is not strictly related to the knee surgery and which may confound the postsurgical assessments (e.g., significant pain from other joints including the non-index knee joint, chronic neuropathic pain, concurrent or prior contralateral TKA, concurrent foot surgery).

4. Previous open knee surgery on the knee being considered for TKA. Prior arthroscopy is permitted.

5. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics.

6. Contraindication to any one of the following: bupivacaine, oxycodone, morphine, or hydromorphone.

7. Use of any of the following medications within the times specified before surgery: long-acting opioid medication or NSAIDs (except for low-dose aspirin used for cardioprotection) within 3 days, or any opioid medication within 24 hours.

8. Initiation of treatment with any of the following medications within 1 month of study drug administration or if the medication(s) are being given to control pain: selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin (Lyrica®), or duloxetine (Cymbalta®). If a subject is taking one of these medications for a reason other than pain control, he or she must be on a stable dose for at least 1 month prior to study drug administration.

9. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study.

10. Use of dexmedetomidine HCl (Precedex®) within 3 days of study drug administration.

11. History of impaired kidney function, poorly controlled chronic respiratory disease, rheumatoid arthritis, coagulopathy, or loss of sensation in extremities.

12. Impaired kidney function (e.g., serum creatinine level >2 mg/dL [176.8 µmol/L] or blood urea nitrogen level >50 mg/dL [17.9 mmol/L]) or impaired liver function (e.g., serum aspartate aminotransferase [AST] level >3 times the upper limit of normal [ULN] or serum alanine aminotransferase [ALT] level >3 times the ULN.)

13. Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments.

14. Any chronic neuromuscular deficit effecting the peripheral nerves or muscles of the surgical extremity.

15. Any chronic condition or disease that would compromise neurological or vascular assessments.

16. Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.

17. Suspected or known history of drug or alcohol abuse within the previous year.

18. Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2.

19. Previous participation in an EXPAREL study.

20. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Horizon Research Group, Inc	Mobile	Alabama	United States	36608
2	Denver Metro Orthopedics	Englewood	Colorado	United States	80113
3	Jackson Memorial Hospital/University of Miami	Miami	Florida	United States	33136
4	Pensacola Research Associates	Pensacola	Florida	United States	32504
5	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02215
7	Montefiore Medical Center	Bronx	New York	United States	10467
8	Fairview Hospital	Cleveland	Ohio	United States
9	Indiana Regional Medical Center	Indiana	Pennsylvania	United States	15701
10	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
11	Chan Soon-Shiong Medical Center	Windber	Pennsylvania	United States	15963
12	Hermann Drive Surgical Hospital	Houston	Texas	United States	77004
13	Westside Surgical Hospital	Houston	Texas	United States	77027
14	Southampton Orthopaedics Sports Medicine	Franklin	Virginia	United States
15	Ziekenhuis Oost-Limburg	Genk		Belgium
16	Aarhus University Hospital	Aarhus C		Denmark
17	Regionshospital Silkeborg	Silkeborg		Denmark

Sponsors and Collaborators

• Pacira Pharmaceuticals, Inc

Investigators

• Study Director: James B Jones, MD, PharmD, Pacira Pharmaceuticals, Inc

Study Documents (Full-Text)

• Statistical Analysis Plan - Jun 20, 2017
• Study Protocol - Nov 7, 2016

More Information

Publications

None provided.

• Responsible Party: Pacira Pharmaceuticals, Inc
• ClinicalTrials.gov Identifier: NCT02713178
• Other Study ID Numbers: 402-C-326
• First Posted: Mar 18, 2016
• Last Update Posted: Dec 1, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Bupivacaine

Study Results

Participant Flow

Recruitment Details	Participants were recruited between June 3, 2016 and June 30, 2017 at 13 sites in the US and Europe

Arm/Group Title	EXPAREL 133 mg	EXPAREL 266 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively	20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively	20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively
Period Title: Overall Study
STARTED	76	77	79
COMPLETED	75	73	74
NOT COMPLETED	1	4	5

Baseline Characteristics

Arm/Group Title	EXPAREL 133 mg	EXPAREL 266 mg	Placebo	Total
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively	20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively	20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively	Total of all reporting groups
Overall Participants	75	76	79	230
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.6 (6.94)	66.0 (9.01)	65.4 (8.69)	65.3 (8.26)
Sex: Female, Male (Count of Participants)
Female	36 48%	43 56.6%	53 67.1%	132 57.4%
Male	39 52%	33 43.4%	26 32.9%	98 42.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.7%	2 2.6%	2 2.5%	6 2.6%
Not Hispanic or Latino	73 97.3%	74 97.4%	75 94.9%	222 96.5%
Unknown or Not Reported	0 0%	0 0%	2 2.5%	2 0.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 1.3%	0 0%	1 0.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	8 10.7%	5 6.6%	12 15.2%	25 10.9%
White	66 88%	69 90.8%	67 84.8%	202 87.8%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.3%	1 1.3%	0 0%	2 0.9%
Region of Enrollment (participants) [Number]
Belgium	36 48%	37 48.7%	36 45.6%	109 47.4%
United States	38 50.7%	38 50%	40 50.6%	116 50.4%
Denmark	1 1.3%	1 1.3%	3 3.8%	5 2.2%
Visual analog scale pain score (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	2.12 (2.656)	2.08 (2.546)	1.80 (2.195)	1.99 (2.458)
American Society of Anesthesiologists classification (Count of Participants)
Score: 1	11 14.7%	9 11.8%	10 12.7%	30 13%
Score: 2	41 54.7%	41 53.9%	46 58.2%	128 55.7%
Score: 3	23 30.7%	26 34.2%	23 29.1%	72 31.3%
Score: Greater than or equal to 4	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores Through 72 Hours
Description	AUC of VAS pain intensity scores through 72 hours. Visual Analog Scale (VAS) is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, "How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now."
Time Frame	0-72 hours

Outcome Measure Data

Analysis Population Description

Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment

Arm/Group Title	EXPAREL 133 mg	EXPAREL 266 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively	20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively	20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively
Measure Participants	75	76	79
Least Squares Mean (Standard Error) [cm*hr]	259.545 (19.011)	250.998 (18.849)	279.794 (18.493)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 133 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4463
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSMD
	Estimated Value	-20.249
	Confidence Interval	(2-Sided) 95%; -72.361 to 31.864
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 266 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2749
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSMD
	Estimated Value	-28.796
	Confidence Interval	(2-Sided) 95%; -80.483 to 22.892
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Total Postsurgical Opioid Consumption Through 72 Hours
Description	Total postsurgical opioid consumption (converted to IV morphine equivalents) through 72 hours
Time Frame	0-72 hours

Outcome Measure Data

Analysis Population Description

Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment

Arm/Group Title	EXPAREL 133 mg	EXPAREL 266 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively	20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively	20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively
Measure Participants	75	76	79
Least Squares Mean (Standard Error) [mg]	69.466 (4.403)	74.393 (4.669)	81.469 (5.006)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 133 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0716
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM treatment ratio
	Estimated Value	0.853
	Confidence Interval	(2-Sided) 95%; 0.717 to 1.014
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 266 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3004
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM treatment ratio
	Estimated Value	0.913
	Confidence Interval	(2-Sided) 95%; 0.769 to 1.084
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Opioid-free Participants Through 72 Hours
Description	Percentage of participants who did not receive opioid medication through 72 hours
Time Frame	0-72 hours

Outcome Measure Data

Analysis Population Description

Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment

Arm/Group Title	EXPAREL 133 mg	EXPAREL 266 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively	20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively	20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively
Measure Participants	75	76	79
Count of Participants [Participants]	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Time to First Opioid Rescue Through 72 Hours
Description	Time to first opioid rescue medication consumed through 72 hours. The "time to rescue" is estimated for each quartile from the Kaplan-Meier analysis, in which first quartile represents the time it took for the first 25% of the population to receive rescue medication, median quartile represents the time it took 50% of the population to receive rescue medication, and third quartile represents the time it took 75% of the population to receive rescue medication.
Time Frame	0-72 hours

Outcome Measure Data

Analysis Population Description

Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment

Arm/Group Title	EXPAREL 133 mg	EXPAREL 266 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively	20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively	20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively
Measure Participants	75	76	79
First quartile	1.80	1.53	1.08
Second quartile	3.03	2.87	2.40
Third quartile	5.07	5.78	3.72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 133 mg, Placebo
	Comments	The overall distribution as estimated by the Kaplan-Meier analysis was compared between the EXPAREL arm and the placebo arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1896
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 266 mg, Placebo
	Comments	The overall distribution as estimated by the Kaplan-Meier analysis was compared between the EXPAREL arm and the placebo arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2549
	Comments
	Method	Log Rank
	Comments

Adverse Events

Time Frame	From screening to day 29 postsurgery
Adverse Event Reporting Description	An adverse event (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	EXPAREL 133 mg		EXPAREL 266 mg		Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively		20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively		20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively
All Cause Mortality
	EXPAREL 133 mg		EXPAREL 266 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/76 (0%)		0/79 (0%)
Serious Adverse Events
	EXPAREL 133 mg		EXPAREL 266 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/75 (6.7%)		8/76 (10.5%)		6/79 (7.6%)
Cardiac disorders
Atrial fibrillation	1/75 (1.3%)		1/76 (1.3%)		1/79 (1.3%)
Bradycardia	0/75 (0%)		0/76 (0%)		1/79 (1.3%)
Sinus arrest	0/75 (0%)		0/76 (0%)		1/79 (1.3%)
Sinus bradycardia	0/75 (0%)		1/76 (1.3%)		0/79 (0%)
General disorders
Chest discomfort	0/75 (0%)		0/76 (0%)		1/79 (1.3%)
Immune system disorders
Anaphylactic shock	0/75 (0%)		1/76 (1.3%)		0/79 (0%)
Infections and infestations
Cellulitis	1/75 (1.3%)		0/76 (0%)		0/79 (0%)
Injury, poisoning and procedural complications
Postprocedural hematoma	3/75 (4%)		1/76 (1.3%)		0/79 (0%)
Postprocedural swelling	1/75 (1.3%)		0/76 (0%)		0/79 (0%)
Investigations
Oxygen saturation decreased	0/75 (0%)		0/76 (0%)		1/79 (1.3%)
Musculoskeletal and connective tissue disorders
Joint swelling	0/75 (0%)		0/76 (0%)		1/79 (1.3%)
Nervous system disorders
Motor dysfunction	0/75 (0%)		2/76 (2.6%)		0/79 (0%)
Transient ischemic attack	0/75 (0%)		1/76 (1.3%)		0/79 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/75 (0%)		1/76 (1.3%)		0/79 (0%)
Respiratory depression	0/75 (0%)		0/76 (0%)		1/79 (1.3%)
Other (Not Including Serious) Adverse Events
	EXPAREL 133 mg		EXPAREL 266 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/75 (97.3%)		74/76 (97.4%)		76/79 (96.2%)
Blood and lymphatic system disorders
Anemia	1/75 (1.3%)		6/76 (7.9%)		5/79 (6.3%)
Gastrointestinal disorders
Nausea	27/75 (36%)		34/76 (44.7%)		24/79 (30.4%)
Constipation	12/75 (16%)		16/76 (21.1%)		15/79 (19%)
Vomiting	4/75 (5.3%)		10/76 (13.2%)		9/79 (11.4%)
Dyspepsia	2/75 (2.7%)		5/76 (6.6%)		2/79 (2.5%)
General disorders
Pyrexia	23/75 (30.7%)		18/76 (23.7%)		22/79 (27.8%)
Peripheral swelling	0/75 (0%)		7/76 (9.2%)		3/79 (3.8%)
Injury, poisoning and procedural complications
Fall	4/75 (5.3%)		5/76 (6.6%)		0/79 (0%)
Postprocedural hematoma	4/75 (5.3%)		1/76 (1.3%)		0/79 (0%)
Investigations
Hepatic enzyme increased	7/75 (9.3%)		1/76 (1.3%)		3/79 (3.8%)
Hemoglobin decreased	1/75 (1.3%)		3/76 (3.9%)		5/79 (6.3%)
Metabolism and nutrition disorders
Hypokalemia	5/75 (6.7%)		5/76 (6.6%)		5/79 (6.3%)
Musculoskeletal and connective tissue disorders
Muscle twitching	5/75 (6.7%)		7/76 (9.2%)		4/79 (5.1%)
Joint swelling	2/75 (2.7%)		2/76 (2.6%)		5/79 (6.3%)
Nervous system disorders
Motor dysfunction	34/75 (45.3%)		35/76 (46.1%)		34/79 (43%)
Dizziness	3/75 (4%)		7/76 (9.2%)		5/79 (6.3%)
Dysgeusia	3/75 (4%)		2/76 (2.6%)		6/79 (7.6%)
Sensory loss	2/75 (2.7%)		6/76 (7.9%)		1/79 (1.3%)
Headache	4/75 (5.3%)		2/76 (2.6%)		0/79 (0%)
Presyncope	0/75 (0%)		0/76 (0%)		4/79 (5.1%)
Psychiatric disorders
Confusional state	1/75 (1.3%)		2/76 (2.6%)		4/79 (5.1%)
Insomnia	1/75 (1.3%)		1/76 (1.3%)		4/79 (5.1%)
Renal and urinary disorders
Urinary retention	3/75 (4%)		10/76 (13.2%)		8/79 (10.1%)
Respiratory, thoracic and mediastinal disorders
Hiccups	4/75 (5.3%)		2/76 (2.6%)		0/79 (0%)
Skin and subcutaneous tissue disorders
Pruritus	4/75 (5.3%)		8/76 (10.5%)		10/79 (12.7%)
Vascular disorders
Hypotension	8/75 (10.7%)		4/76 (5.3%)		5/79 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

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.