TKA: Dose-Ranging Study for Prolonged Postoperative Analgesia in Subject Undergoing Total Knee Arthroplasty

• Sponsor: Pacira Pharmaceuticals, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00485693
• Collaborator: (none)
• Enrollment: 138
• Locations: 9
• Arms: 2
• Duration (Months): 26
• Patients Per Site: 15.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Dose-ranging study for prolonged postoperative analgesia in subjects undergoing total knee arthroplasty

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain	Drug: Bupivacaine HCl; Drug: SKY0402	Phase 2

Detailed Description

This is a phase 2, multicenter, parallel-group, active-control, randomized, double-blind, dose-ranging study conducted to evaluate three dose levels of SKY0402 compared with 150 mg of bupivacaine HCl.

Study Design

• Study Type: Interventional
• Actual Enrollment: 138 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Multicenter, Randomized, Double-blind, Parallel-group, Active-control, Dose-ranging Study to Evaluate the Safety, Efficacy, and Comparative Systemic Bioavailability of a Single Administration of SKY0402 Via Local Infiltration for Prolonged Postoperative Analgesia in Subjects Undergoing Total Knee Arthroplasty.
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bupivacaine HCl Bupivacaine HCl (Marcaine 0.25% with epinephrine 1:200,000)	Drug: Bupivacaine HCl; 150 mg Bupivacaine HCl; Other Names: Bupivacaine HCl (Marcaine 0.25% with epinephrine 1:200,000)
Other: SKY0402 SKY0402 at various dosage levels. Single administration.	Drug: SKY0402; 600 mg SKY0402 (study drug); Other Names: EXPAREL

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) With Activity (NRS-A) Pain Intensity Scores Through Postoperative Day 4 [0 to 96 hours]

   The subject's pain intensity was to be assessed with activity (NRS-A) after actively flexing the involved knee to the maximum flexion point possible. The subject was asked to respond to the following question: "On a scale of 0 to 10, where 0 = no pain and 10 = worst possible pain, how much pain did you have while bending your knee?"

Secondary Outcome Measures

1. Number of Participants With Adverse Events or Serious Adverse Events Through 30 Days [Up to 30 days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female, greater than or equal to 18 and less than or equal to 75 years of age at the Screening Visit.

2. Female subjects only: Postmenopausal, surgically sterile, or willing to use acceptable means of contraception for at least 30 days after surgery including any of the following: hormonal contraceptives (e.g., oral, injectable, implantable starting at least 30 days before study drug administration), effective double-barrier methods (e.g., condoms with spermicide), intrauterine device, lifestyle with a personal choice of abstinence, nonheterosexual lifestyle, or a strictly monogamous relationship with a partner who has had a vasectomy.

3. Scheduled to undergo primary unilateral total knee arthroplasty (TKA) under general anesthesia.

4. American Society of Anesthesiology (ASA) Physical Class 1-3.

5. Able and willing to comply with all study visits and procedures.

6. Able to speak, read, and understand the language of the Informed Consent, study questionnaires, and other instruments used for collecting subject-reported outcomes, in order to enable accurate and appropriate responses to pain scales and other required study assessments.

7. Willing and capable of providing written informed consent.

Exclusion Criteria:

1. Pregnancy, nursing, or planning to become pregnant during the study or within one month after dosing.

2. Use of any of the following medications within the times specified before surgery:

• Long-acting opioid medication within 3 days.

• Any opioid medication within 24 hours.

1. Concurrent, painful, physical condition or concurrent surgery that may require analgesic treatment in the postoperative period for pain that is not strictly related to the surgical site administered study treatment, and which may confound the postoperative assessments (e.g., significant pain from other joints, chronic neuropathic pain, concurrent contralateral TKA, concurrent foot surgery, etc.).

2. Body weight less than 50 kilograms (110 pounds) or morbid obesity.

3. Contraindication to any of the pain-control agents planned for postoperative use (e.g., acetaminophen, morphine, oxycodone, ketorolac).

4. Contraindication to epinephrine, such as concurrent administration of monoamine oxidase (MAO) inhibitors or antidepressants of amitriptyline or imipramine types, conditions where the production or exacerbation of tachycardia could prove fatal (e.g., poorly controlled thyrotoxicosis or severe heart disease), or any other pathological conditions that might be aggravated by the effects of epinephrine.

5. 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.

6. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past 2 years.

7. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of the Investigator, may interfere with study assessments or compliance.

8. 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 postoperative course.

9. Significant medical conditions or laboratory results that, in the opinion of the Investigator, indicate an increased vulnerability to study drugs and procedures, and expose the subject to an unreasonable risk as a result of participating in this clinical trial, such as: debilitating diseases, acute illnesses, hypotension, partial or complete conduction block, impaired cardiac function, untreated hypertension, advanced arteriosclerotic heart disease, cerebral vascular insufficiency, pre-existing abnormal neurological or neuromuscular disease (e.g., epilepsy, myasthenia gravis), advanced liver disease, severe renal impairment, advanced diabetes comorbid conditions associated with an immunocompromised status, such as blood dyscrasias, HIV/AIDS, or recent chemotherapy.

In addition, the subject will be ineligible to receive study drug if he or she meets the following criteria during surgery:

1. Any clinically significant event or condition uncovered during surgery(e.g., excessive bleeding), which occurs before study drug administration, that might render the subject medically unstable or complicate the subject's postoperative course.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	West Alabama Research, Inc.	Birmingham	Alabama	United States	35209
2	California Clinical Research, Inc.	Davis	California	United States	95616
3	Accurate Clinical Trials, Inc.	Laguna Hills	California	United States	92653
4	St. Luke's Roosevelt Hospital	New York	New York	United States	10019
5	The Ohio State University Medical Center	Columbus	Ohio	United States	43220
6	Texas Tech University Health Science Center	Lubbock	Texas	United States	79430
7	Urazova Nemocnice Brno	Brno		Czechia	66250
8	Regional Hospital Kladno	Kladno		Czechia	1548
9	The Hospital Trebic	Třebíč		Czechia	67401

Sponsors and Collaborators

• Pacira Pharmaceuticals, Inc

Investigators

• Study Director: Joyce Davis, RN, Pacira Pharmaceuticals, Inc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pacira Pharmaceuticals, Inc
• ClinicalTrials.gov Identifier: NCT00485693
• Other Study ID Numbers: SKY0402C208
• First Posted: Jun 13, 2007
• Last Update Posted: Jun 28, 2022
• Last Verified: Jun 1, 2022

• Keywords provided by Pacira Pharmaceuticals, Inc: pain; postoperative; total knee arthroplasty; analgesia
• Additional relevant MeSH terms: Pain, Postoperative; Epinephrine; Bupivacaine

Study Results

Participant Flow

Arm/Group Title	Bupivacaine HCl	SKY0402
Arm/Group Description	A single dose of study drug was to be administered intraoperatively via local infiltration	A single dose of study drug was to be administered intraoperatively via local infiltration
Period Title: Overall Study
STARTED	34	104
COMPLETED	34	104
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Bupivacaine HCl	SKY0402	Total
Arm/Group Description	A single dose of study drug was to be administered intraoperatively via local infiltration	A single dose of study drug was to be administered intraoperatively via local infiltration	Total of all reporting groups
Overall Participants	34	104	138
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	22 64.7%	67 64.4%	89 64.5%
>=65 years	12 35.3%	37 35.6%	49 35.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.2 (7.2)	62.3 (7.4)	62.2 (7.3)
Sex: Female, Male (Count of Participants)
Female	23 67.6%	62 59.6%	85 61.6%
Male	11 32.4%	42 40.4%	53 38.4%
Region of Enrollment (participants) [Number]
United States	28 82.4%	69 66.3%	97 70.3%
Czech Republic	6 17.6%	35 33.7%	41 29.7%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) With Activity (NRS-A) Pain Intensity Scores Through Postoperative Day 4
Description	The subject's pain intensity was to be assessed with activity (NRS-A) after actively flexing the involved knee to the maximum flexion point possible. The subject was asked to respond to the following question: "On a scale of 0 to 10, where 0 = no pain and 10 = worst possible pain, how much pain did you have while bending your knee?"
Time Frame	0 to 96 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bupivacaine HCl	SKY0402 Low Dose	SKY0402 Low-mid Dose	SKY0402 High-mid Dose	SKY0402 High Dose
Arm/Group Description	Single administration of 150 mg bupivacaine HCl in a 60-mL injection volume (undiluted)	Single administration of SKY0402150 mg in a volume of 60 mL via local infiltration	Single administration of SKY0402 300mg in a volume of 60 mL via local infiltration	Single administration of SKY0402 450 mg in a volume of 60 mL via local infiltration	Single administration of SKY0402 600mg in a volume of 60 mL via local infiltration
Measure Participants	34	28	25	26	25
Mean (Standard Deviation) [Units on a scale*hours]	20.4 (3.9)	20.7 (5.4)	19.5 (5.3)	18.8 (5.3)	19.1 (4.4)

2. Secondary Outcome

Title	Number of Participants With Adverse Events or Serious Adverse Events Through 30 Days
Time Frame	Up to 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Bupivacaine HCl		SKY0402
Arm/Group Description	A single dose of study drug was to be administered intraoperatively via local infiltration		A single dose of study drug was to be administered intraoperatively via local infiltration
All Cause Mortality
	Bupivacaine HCl		SKY0402
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/34 (2.9%)		1/104 (1%)
Serious Adverse Events
	Bupivacaine HCl		SKY0402
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/34 (8.8%)		5/104 (4.8%)
Gastrointestinal disorders
Haematemesis	0/34 (0%)	0	1/104 (1%)	1
Infections and infestations
Bronchitis	1/34 (2.9%)	1	0/104 (0%)	0
Haematoma infection	1/34 (2.9%)	1	0/104 (0%)	0
Injury, poisoning and procedural complications
Post procedural haemorrhage	0/34 (0%)	0	1/104 (1%)	1
Nervous system disorders
Sedation	0/34 (0%)	0	1/104 (1%)	1
Psychiatric disorders
Bipolar disorder	0/34 (0%)	0	1/104 (1%)	1
Renal and urinary disorders
Cystitis haemorrhagic	0/34 (0%)	0	1/104 (1%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/34 (0%)	0	1/104 (1%)	1
Pulmonary embolism	1/34 (2.9%)	1	0/104 (0%)	0
Respiratory depression	0/34 (0%)	0	1/104 (1%)	1
Other (Not Including Serious) Adverse Events
	Bupivacaine HCl		SKY0402
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/34 (85.3%)		83/104 (79.8%)
Blood and lymphatic system disorders
Haemorrhagic anaemia	8/34 (23.5%)		25/104 (24%)
Anaemia	6/34 (17.6%)		16/104 (15.4%)
Cardiac disorders
Tachycardia	4/34 (11.8%)		18/104 (17.3%)
Gastrointestinal disorders
Nausea	23/34 (67.6%)		48/104 (46.2%)
Constipation	13/34 (38.2%)		36/104 (34.6%)
Vomiting	6/34 (17.6%)		16/104 (15.4%)
General disorders
Pyrexia	11/34 (32.4%)		38/104 (36.5%)
Oedema peripheral	11/34 (32.4%)		30/104 (28.8%)
Fatigue	4/34 (11.8%)		5/104 (4.8%)
Injury, poisoning and procedural complications
Anaemia postoperative	7/34 (20.6%)		13/104 (12.5%)
Musculoskeletal and connective tissue disorders
Muscle spasms	3/34 (8.8%)		6/104 (5.8%)
Nervous system disorders
Dizziness	6/34 (17.6%)		13/104 (12.5%)
Somnolence	1/34 (2.9%)	1	11/104 (10.6%)	1
Headache	2/34 (5.9%)		5/104 (4.8%)
Lethargy	0/34 (0%)	0	7/104 (6.7%)	0
Psychiatric disorders
Insomnia	5/34 (14.7%)		11/104 (10.6%)
Respiratory, thoracic and mediastinal disorders
Cough	0/34 (0%)	0	6/104 (5.8%)	0
Pharyngolaryngeal pain	2/34 (5.9%)		4/104 (3.8%)
Skin and subcutaneous tissue disorders
Pruritis	6/34 (17.6%)		10/104 (9.6%)
Vascular disorders
Hypotension	12/34 (35.3%)		21/104 (20.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.