TKA: A Phase 3 Study to Evaluate the Safety and Efficacy of SKY0402 in Subjects Undergoing Total Knee Arthroplasty

• Sponsor: Pacira Pharmaceuticals, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00745290
• Collaborator: (none)
• Enrollment: 245
• Locations: 19
• Arms: 2
• Duration (Months): 6
• Patients Per Site: 12.9
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

The primary objective is to demonstrate that SKY0402 is superior when compared to bupivacaine HCl in the management of postoperative pain for patients undergoing total knee arthroplasty.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain	Drug: Bupivacaine HCl; Drug: SKY0402	Phase 3

Detailed Description

The primary objective is to demonstrate the superiority of SKY0402, compared with bupivacaine HC1, with respect to the extent and duration of the analgesic effect achieved by a single intraoperative administration of the study drug via local infiltration in subjects undergoing total knee arthroplasty (TKA).

The secondary objectives are to evaluate additional efficacy parameters and characterize the safety profile of SKY0402 in comparison with bupivacaine HCl.

Study Design

• Study Type: Interventional
• Actual Enrollment: 245 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Active Control Study to Evaluate the Safety and Efficacy of a Single Intraoperative Administration of SKY0402 For Prolonged Postoperative Analgesia in Subject Undergoing Total Knee Arthroplasty
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bupivacaine HCl Single dose of 200 mg bupivacaine HCl administered intraoperatively via local infiltration	Drug: Bupivacaine HCl; 200 mg bupivacaine HCl; Other Names: Marcaine
Other: SKY0402 Single dose of 600 mg SKY0402 (study drug) administered intraoperatively via local infiltration	Drug: SKY0402; 600 mg SKY0402 (study drug).; Other Names: DepoBupivacaine

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 72 hours post surgery]

   The subject's pain intensity was assessed with activity (NRS-A), while actively flexing the involved knee from the maximum extension point to the maximum flexion point possible. The subject responded 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 Through 96 Hours and Serious Adverse Events Through 30 Days [through 30 days]

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, ≥18 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 TKA under general or spinal anesthesia.

4. American Society of Anesthesiology (ASA) Physical Classification System class 1-4.

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 form, 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 being administered study drug (e.g., significant pain from other joints, chronic neuropathic pain, concurrent contralateral TKA, concurrent foot surgery, etc.), which have the potential to confound the postoperative study assessments.

2. Body weight less than 60 kilograms (~132 pounds).

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 ergot-type drugs, monoamine oxidase (MAO) inhibitors or antidepressants of triptoline 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. 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 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 criterion 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	Horizon Research Group, Inc., Alabama Orthopaedic Clinic	Mobile	Alabama	United States	36608
3	Drug Research and Analysis Corporation	Montgomery	Alabama	United States	36106
4	Sun Health Research Institute, Core Institute	Sun City West	Arizona	United States	85375
5	Scripps	La Jolla	California	United States	92037
6	Accurate Clinical Trials, Inc.	Laguna Hills	California	United States	92653
7	Physicans Clinical Research Corp.	Laguna Hills	California	United States	92653
8	Cedars of Sinai Medical Center	Los Angeles	California	United States	90048
9	Atlanta Knee and Sports Medicine	Decatur	Georgia	United States	30033
10	Rush University Medical Center	Chicago	Illinois	United States	60612
11	Insall Scott Kelly Institute	New York	New York	United States	10065
12	CTMG, Inc.	Greenville	North Carolina	United States	27834
13	Duke University Medical Center	Raleigh-Durham	North Carolina	United States	27710
14	Ohio State University Medical Center	Columbus	Ohio	United States	43210
15	Allegheny Pain Management	Altoona	Pennsylvania	United States	16602
16	Ilumina Clinical Associates	Johnstown	Pennsylvania	United States	15904
17	Research Associates of Jackson	Jackson	Tennessee	United States	38301
18	Texas Orthopedic Specialists, PA	Grapevine	Texas	United States	76051
19	Memorial Hermann City Hospital	Houston	Texas	United States	77024

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: NCT00745290
• Other Study ID Numbers: SIMPLE TKA 311
• First Posted: Sep 3, 2008
• Last Update Posted: Aug 6, 2013
• Last Verified: Jul 1, 2013

• Keywords provided by Pacira Pharmaceuticals, Inc: Total knee arthroplasty; Pain; Analgesia
• Additional relevant MeSH terms: Pain, Postoperative; Bupivacaine

Study Results

Participant Flow

Arm/Group Title	Bupivacaine HCl	SKY0402
Arm/Group Description	randomized in a 1:1 ratio to receive 200 mg bupivacaine HCl and stratified by site and by modality.	randomized in a 1:1 ratio to receive 600 mg SKY0402 (study drug) and stratified by site and by modality.
Period Title: Overall Study
STARTED	123	122
COMPLETED	123	122
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Bupivacaine HCl	SKY0402	Total
Arm/Group Description	randomized in a 1:1 ratio to receive 200 mg bupivacaine HCl and stratified by site and by modality.	randomized in a 1:1 ratio to receive 600 mg SKY0402 (study drug) and stratified by site and by modality.	Total of all reporting groups
Overall Participants	123	122	245
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	67 54.5%	52 42.6%	119 48.6%
>=65 years	56 45.5%	70 57.4%	126 51.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.8 (10.4)	66.8 (10.6)	65.8 (10.5)
Sex: Female, Male (Count of Participants)
Female	73 59.3%	83 68%	156 63.7%
Male	50 40.7%	39 32%	89 36.3%
Region of Enrollment (participants) [Number]
United States	123 100%	122 100%	245 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) With Activity (NRS-A) Pain Intensity Scores
Description	The subject's pain intensity was assessed with activity (NRS-A), while actively flexing the involved knee from the maximum extension point to the maximum flexion point possible. The subject responded 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	through 72 hours post surgery

Outcome Measure Data

Analysis Population Description

Note: 245 subjects were randomized and received study drug and were included in the analyses.

Arm/Group Title	Bupivacaine HCl	SKY0402
Arm/Group Description	randomized in a 1:1 ratio to receive 200 mg bupivacaine HCl and stratified by site and by modality.	randomized in a 1:1 ratio to receive 600 mg SKY0402 (study drug) and stratified by site and by modality.
Measure Participants	123	122
Mean (Standard Deviation) [Units on a scale*hours]	335 (113)	359 (124)

2. Secondary Outcome

Title	Number of Participants With Adverse Events Through 96 Hours and Serious Adverse Events Through 30 Days
Time Frame	through 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	randomized in a 1:1 ratio to receive 200 mg bupivacaine HCl and stratified by site and by modality.		randomized in a 1:1 ratio to receive 600 mg SKY0402 (study drug) and stratified by site and by modality.
All Cause Mortality
	Bupivacaine HCl		SKY0402
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bupivacaine HCl		SKY0402
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/123 (14.6%)		12/122 (9.8%)
Cardiac disorders
Atrial fibrillation	2/123 (1.6%)		0/122 (0%)	0
Cardiac failure congestive	0/123 (0%)	0	2/122 (1.6%)	0
Myocardial Infarction	0/123 (0%)	0	1/122 (0.8%)	1
Gastrointestinal disorders
Gastrointestinal hemorrhage	1/123 (0.8%)		0/122 (0%)	0
General disorders
Adverse drug reaction	1/123 (0.8%)	1	0/122 (0%)	0
Chest pain	0/123 (0%)	0	1/122 (0.8%)	1
Infections and infestations
Cellulitis	0/123 (0%)	0	3/122 (2.5%)	0
Postoperative wound infection	1/123 (0.8%)	1	1/122 (0.8%)	1
Urinary tract infection	1/123 (0.8%)	1	0/122 (0%)	0
Injury, poisoning and procedural complications
Femur fracture	1/123 (0.8%)	1	0/122 (0%)	0
Postprocedural hematoma	1/123 (0.8%)	1	0/122 (0%)	0
Metabolism and nutrition disorders
Hypoglycemia	2/123 (1.6%)		0/122 (0%)	0
Dehydration	1/123 (0.8%)		0/122 (0%)	0
Hyperglycemia	1/123 (0.8%)		0/122 (0%)	0
Musculoskeletal and connective tissue disorders
Arthrofibrosis	3/123 (2.4%)		0/122 (0%)	0
Haemarthrosis	1/123 (0.8%)	1	0/122 (0%)	0
Joint swelling	1/123 (0.8%)	1	0/122 (0%)	0
Nervous system disorders
Embolic stroke	0/123 (0%)	0	1/122 (0.8%)	1
Peroneal nerve palsy	1/123 (0.8%)		0/122 (0%)	0
Sedation	0/123 (0%)		1/122 (0.8%)	1
Syncope	1/123 (0.8%)		0/122 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hiccups	0/123 (0%)	0	1/122 (0.8%)	1
Respiratory failure	0/123 (0%)	0	1/122 (0.8%)	1
Skin and subcutaneous tissue disorders
Blood blister	0/123 (0%)	0	1/122 (0.8%)	1
Surgical and medical procedures
Knee arthroplasty	1/123 (0.8%)	1	0/122 (0%)	0
Vascular disorders
Deep vein thrombosis	2/123 (1.6%)		0/122 (0%)	0
Other (Not Including Serious) Adverse Events
	Bupivacaine HCl		SKY0402
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	107/123 (87%)		108/122 (88.5%)
Blood and lymphatic system disorders
Haemorrhagic anemia	8/123 (6.5%)		4/122 (3.3%)
Anemia	28/123 (22.8%)		28/122 (23%)
Cardiac disorders
Tachycardia	3/123 (2.4%)		7/122 (5.7%)
Gastrointestinal disorders
Nausea	71/123 (57.7%)		76/122 (62.3%)
Constipation	47/123 (38.2%)		56/122 (45.9%)
Vomiting	42/123 (34.1%)		38/122 (31.1%)
General disorders
Pyrexia	16/123 (13%)		14/122 (11.5%)
Oedema peripheral	5/123 (4.1%)		9/122 (7.4%)
Injury, poisoning and procedural complications
Anemia postoperative	10/123 (8.1%)		12/122 (9.8%)
Procedural pain	9/123 (7.3%)		10/122 (8.2%)
Nervous system disorders
Dizziness	3/123 (2.4%)		8/122 (6.6%)
Psychiatric disorders
Insomnia	9/123 (7.3%)		9/122 (7.4%)
Skin and subcutaneous tissue disorders
Pruritis	16/123 (13%)		11/122 (9%)
Vascular disorders
Hypotension	4/123 (3.3%)		9/122 (7.4%)

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.