Postoperative Pain
Conditions
Keywords
Total knee arthroplasty, Pain, Analgesia
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.
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.
Interventions
DRUGBupivacaine HCl
200 mg bupivacaine HCl
DRUGSKY0402
600 mg SKY0402 (study drug).
Sponsors
Pacira Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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. 3. 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. 4. Body weight less than 60 kilograms (\ 132 pounds). 5. Contraindication to any of the pain-control agents planned for postoperative use (e.g., acetaminophen, morphine, oxycodone, ketorolac). 6. 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. 7. 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. 8. Suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past 2 years. 9. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of the Investigator, may interfere with study assessments or compliance. 10. 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. 11. 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: 12. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| Number of Participants With Adverse Events Through 96 Hours and Serious Adverse Events Through 30 Days | through 30 days |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bupivacaine HCl randomized in a 1:1 ratio to receive 200 mg bupivacaine HCl and stratified by site and by modality. | 123 |
| SKY0402 randomized in a 1:1 ratio to receive 600 mg SKY0402 (study drug) and stratified by site and by modality. | 122 |
| Total | 245 |
Baseline characteristics
| Characteristic | SKY0402 | Bupivacaine HCl | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 70 Participants | 56 Participants | 126 Participants |
| Age, Categorical Between 18 and 65 years | 52 Participants | 67 Participants | 119 Participants |
| Age Continuous | 66.8 years STANDARD_DEVIATION 10.6 | 64.8 years STANDARD_DEVIATION 10.4 | 65.8 years STANDARD_DEVIATION 10.5 |
| Region of Enrollment United States | 122 participants | 123 participants | 245 participants |
| Sex: Female, Male Female | 83 Participants | 73 Participants | 156 Participants |
| Sex: Female, Male Male | 39 Participants | 50 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 107 / 123 | 108 / 122 |
| serious Total, serious adverse events | 18 / 123 | 12 / 122 |
Outcome results
Primary
Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) With Activity (NRS-A) Pain Intensity Scores
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
Population: Note: 245 subjects were randomized and received study drug and were included in the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bupivacaine HCl | Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) With Activity (NRS-A) Pain Intensity Scores | 335 Units on a scale*hours | Standard Deviation 113 |
| SKY0402 | Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) With Activity (NRS-A) Pain Intensity Scores | 359 Units on a scale*hours | Standard Deviation 124 |
Secondary
Number of Participants With Adverse Events Through 96 Hours and Serious Adverse Events Through 30 Days
Time frame: through 30 days