Postoperative Pain
Conditions
Keywords
knee, knee replacement, arthroplasty, joint replacement, knee pain
Brief summary
This is a Phase 2b, randomized, double-blind, saline placebo- and active-controlled, multicenter study in subjects undergoing primary unilateral total knee arthroplasty (TKA) to evaluate the analgesic efficacy, safety, and pharmacokinetics (PK) of HTX-011 administered via infiltration to the surgical site.
Interventions
DRUGHTX-011
HTX-011 (bupivacaine/meloxicam), via instillation
DRUGSaline Placebo
Saline placebo via injection
DRUGBupivicaine HCl
Bupivacaine HCl without epinephrine
DRUGRopivacaine
Ropivacaine, via injection
Sponsors
Heron Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Is scheduled to undergo primary unilateral TKA under general anesthesia. * Has not previously undergone TKA in either knee. * Has an American Society of Anesthesiologists Physical Status of I, II, or III. * Is able to demonstrate motor function by performing a timed 20-meter walk unassisted, but with the optional use of a 4-legged walker for balance. * Female subjects are eligible only if not pregnant, not lactating, not planning to become pregnant during the study, sterile; or using acceptable contraceptives.
Exclusion criteria
* Has a planned concurrent surgical procedure (eg, bilateral TKA). * Has a pre-existing concurrent acute or chronic painful/restrictive physical condition that may require analgesic treatment in the postoperative period for pain. * Has a contraindication or a known or suspected history of hypersensitivity or idiosyncratic reaction to required study medications. * Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 6 months. * Has taken NSAIDs within 10 days prior to the scheduled surgery. * Has taken opioids within 24 hours prior to the scheduled surgery (3 days for long-acting). * Has been administered bupivacaine within 5 days prior to the scheduled surgery. * Has initiated treatment with medications within 1 month prior to study drug administration that can impact pain control. * Has been administered systemic steroids within 5 half-lives or 10 days prior to administration of study drug. * Has a medical condition such that, in the opinion of the Investigator, participating in the study would pose a health risk to the subject or confound the postoperative assessments. * Has a known history of Hepatitis B, human immunodeficiency virus (HIV), or active Hepatitis C. * Has uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments. * Has any chronic neuromuscular deficit of either femoral nerve function or thigh musculature. Has any chronic condition or disease that would compromise neurological or vascular assessments. * Had a malignancy in the last year, with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. * Has a known or suspected history of drug abuse, a positive drug screen on the day of surgery, or a recent history of alcohol abuse. * Received an investigational product or device in a clinical trial within 30 days or within 5 elimination half lives. * Has undergone 3 or more surgeries within 12 months. * Has a body mass index (BMI) \>38 kg/m2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). | 48 hours | Pain intensity is assessed at rest using an 11-point NRS (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable" (using windowed worst observation carried forward to adjust for opioid rescue medication use). The theoretical range of AUC0-48 is 0-480. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). | 72 hours | Pain intensity is assessed at rest using an 11-point NRS (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable" (using windowed worst observation carried forward to adjust for opioid rescue medication use). The theoretical range of AUC0-72 is 0-720. |
| Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 72 hours | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1, Group 1: HTX-011 HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg via instillation. | 20 |
| Cohort 1, Group 2: HTX-011 HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg via injection and instillation (combination). | 22 |
| Cohort 1, Group 3: Saline Placebo Saline placebo via injection. | 11 |
| Cohort 1, Group 4: Bupivacaine HCI Bupivacaine HCl without epinephrine, 125 mg via injection. | 10 |
| Cohort 2, Group 1: HTX-011 HTX-011(bupivacaine/meloxicam), 400 mg/12 mg via instillation. | 58 |
| Cohort 2, Group 2: HTX-011 + Ropivacaine HTX-011(bupivacaine/meloxicam), 400 mg/12 mg via instillation; Ropivacaine, 50 mg via injection. | 56 |
| Cohort 2, Group 3: Saline Placebo Saline placebo via injection. | 53 |
| Cohort 2, Group 4: Bupivacaine HCI Bupivacaine HCl without epinephrine, 125 mg via injection. | 55 |
| Total | 285 |
Baseline characteristics
| Characteristic | Cohort 1, Group 2: HTX-011 | Cohort 1, Group 3: Saline Placebo | Cohort 1, Group 4: Bupivacaine HCI | Cohort 2, Group 1: HTX-011 | Cohort 2, Group 2: HTX-011 + Ropivacaine | Cohort 2, Group 3: Saline Placebo | Cohort 1, Group 1: HTX-011 | Cohort 2, Group 4: Bupivacaine HCI | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 6 Participants | 6 Participants | 27 Participants | 22 Participants | 17 Participants | 8 Participants | 17 Participants | 108 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 5 Participants | 4 Participants | 31 Participants | 34 Participants | 36 Participants | 12 Participants | 38 Participants | 177 Participants |
| Age, Continuous | 58.6 years STANDARD_DEVIATION 7.44 | 64.9 years STANDARD_DEVIATION 4.64 | 65.3 years STANDARD_DEVIATION 11.62 | 62.5 years STANDARD_DEVIATION 8.63 | 63.2 years STANDARD_DEVIATION 9.36 | 61.5 years STANDARD_DEVIATION 8.31 | 62.1 years STANDARD_DEVIATION 7.52 | 61.4 years STANDARD_DEVIATION 9.37 | 62.1 years STANDARD_DEVIATION 8.71 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 3 Participants | 1 Participants | 9 Participants | 16 Participants | 12 Participants | 7 Participants | 16 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 8 Participants | 9 Participants | 49 Participants | 40 Participants | 41 Participants | 13 Participants | 39 Participants | 211 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 3 Participants | 6 Participants | 5 Participants | 8 Participants | 5 Participants | 7 Participants | 39 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 9 Participants | 7 Participants | 51 Participants | 49 Participants | 45 Participants | 15 Participants | 47 Participants | 241 Participants |
| Region of Enrollment United States | 22 participants | 11 participants | 10 participants | 58 participants | 56 participants | 53 participants | 20 participants | 55 participants | 285 participants |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 5 Participants | 26 Participants | 27 Participants | 25 Participants | 13 Participants | 35 Participants | 147 Participants |
| Sex: Female, Male Male | 13 Participants | 4 Participants | 5 Participants | 32 Participants | 29 Participants | 28 Participants | 7 Participants | 20 Participants | 138 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 22 | 0 / 11 | 0 / 10 | 0 / 58 | 0 / 56 | 0 / 53 | 0 / 55 |
| other Total, other adverse events | 19 / 20 | 22 / 22 | 11 / 11 | 10 / 10 | 55 / 58 | 50 / 56 | 50 / 53 | 49 / 55 |
| serious Total, serious adverse events | 0 / 20 | 2 / 22 | 0 / 11 | 1 / 10 | 1 / 58 | 4 / 56 | 3 / 53 | 2 / 55 |
Outcome results
Primary
Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48).
Pain intensity is assessed at rest using an 11-point NRS (0-10) where 0 represents no pain and 10 represents worst pain imaginable (using windowed worst observation carried forward to adjust for opioid rescue medication use). The theoretical range of AUC0-48 is 0-480.
Time frame: 48 hours
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, Group 1: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). | 386.12 pain intensity score*hr | Standard Deviation 82.93 |
| Cohort 1, Group 2: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). | 391.56 pain intensity score*hr | Standard Deviation 84.45 |
| Cohort 1, Group 3: Saline Placebo | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). | 405.82 pain intensity score*hr | Standard Deviation 97.549 |
| Cohort 1, Group 4: Bupivacaine HCI | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). | 347.56 pain intensity score*hr | Standard Deviation 103.422 |
| Cohort 2, Group 1: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). | 322.08 pain intensity score*hr | Standard Deviation 99.669 |
| Cohort 2, Group 2: HTX-011 + Ropivacaine | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). | 307.25 pain intensity score*hr | Standard Deviation 127.674 |
| Cohort 2, Group 3: Saline Placebo | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). | 396.36 pain intensity score*hr | Standard Deviation 77.468 |
| Cohort 2, Group 4: Bupivacaine HCI | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 48 Hours Postsurgery (AUC0-48). | 352.74 pain intensity score*hr | Standard Deviation 100.887 |
Secondary
Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72).
Pain intensity is assessed at rest using an 11-point NRS (0-10) where 0 represents no pain and 10 represents worst pain imaginable (using windowed worst observation carried forward to adjust for opioid rescue medication use). The theoretical range of AUC0-72 is 0-720.
Time frame: 72 hours
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, Group 1: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). | 543.14 pain intensity score*hr | Standard Deviation 142.566 |
| Cohort 1, Group 2: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). | 560.85 pain intensity score*hr | Standard Deviation 136.099 |
| Cohort 1, Group 3: Saline Placebo | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). | 576.44 pain intensity score*hr | Standard Deviation 150.815 |
| Cohort 1, Group 4: Bupivacaine HCI | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). | 468.58 pain intensity score*hr | Standard Deviation 179.687 |
| Cohort 2, Group 1: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). | 471.19 pain intensity score*hr | Standard Deviation 149.443 |
| Cohort 2, Group 2: HTX-011 + Ropivacaine | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). | 452.54 pain intensity score*hr | Standard Deviation 194.095 |
| Cohort 2, Group 3: Saline Placebo | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). | 577.93 pain intensity score*hr | Standard Deviation 125.102 |
| Cohort 2, Group 4: Bupivacaine HCI | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores at Rest (NRS-R) Through 72 Hours Postsurgery (AUC0-72). | 516.93 pain intensity score*hr | Standard Deviation 152.512 |
Secondary
Mean Total Postoperative Opioid Consumption (in Morphine Equivalents)
Time frame: 72 hours
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, Group 1: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 65.53 morphine milligram equivalent (MME) | Standard Deviation 31.615 |
| Cohort 1, Group 2: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 66.86 morphine milligram equivalent (MME) | Standard Deviation 31.154 |
| Cohort 1, Group 3: Saline Placebo | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 70.41 morphine milligram equivalent (MME) | Standard Deviation 18.057 |
| Cohort 1, Group 4: Bupivacaine HCI | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 60.70 morphine milligram equivalent (MME) | Standard Deviation 29.903 |
| Cohort 2, Group 1: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 64.39 morphine milligram equivalent (MME) | Standard Deviation 27.889 |
| Cohort 2, Group 2: HTX-011 + Ropivacaine | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 60.32 morphine milligram equivalent (MME) | Standard Deviation 34.949 |
| Cohort 2, Group 3: Saline Placebo | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 73.55 morphine milligram equivalent (MME) | Standard Deviation 34.448 |
| Cohort 2, Group 4: Bupivacaine HCI | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 68.35 morphine milligram equivalent (MME) | Standard Deviation 29.169 |