Postoperative Pain
Conditions
Keywords
bunion, bunionectomy, bunion surgery, postoperative pain
Brief summary
This is a Phase 3, randomized, double-blind, saline placebo- and active-controlled, multicenter study to evaluate the analgesic efficacy and safety of HTX 011 administered via local administration into the surgical site in subjects undergoing bunionectomy.
Interventions
DRUGHTX-011
HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation
DRUGSaline Placebo
Saline placebo by instillation
DRUGBupivacaine HCl
Bupivacaine HCl without epinephrine, 50 mg by injection
DEVICELuer-lock applicator
Applicator for instillation
DEVICEVial access device
Device for withdrawal of drug product
Sponsors
Heron Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Is scheduled to undergo a primary unilateral, distal, first metatarsal bunionectomy with osteotomy and internal fixation under regional anesthesia. * Has an American Society of Anesthesiologists Physical Status of I, II, or III. * 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 had a contralateral foot bunionectomy in the past 3 months. * Has a planned concurrent surgical procedure (eg, bilateral bunionectomy or collateral procedures on the surgical foot). * Has other pre existing concurrent acute or chronic painful physical/restrictive condition expected to require analgesic treatment in the postoperative period for pain. * Has a contraindication or a known or suspected history of hypersensitivity or clinically significant 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 any NSAIDs within at least 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. * As per subject history and/or medical records, has active infection or is currently undergoing treatment for Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV). * Has uncontrolled anxiety, psychiatric, or neurological disorder. * Had a malignancy in the last year, with the exception of nonmetastatic 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. Note: Subjects with a positive drug screen who are taking an allowed, prescribed medication that is known to result in a positive drug test (eg, amphetamine and dextroamphetamine for attention deficit/hyperactivity disorder, benzodiazepine for anxiety disorder) may be eligible for participation in the study. Subjects taking medical marijuana are not allowed to participate in the study. * 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) \>39 kg/m2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 72 Hours Postsurgery (AUC0-72), Compared With Saline Placebo. | 72 hours | Pain intensity is assessed 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. The prescribed activity for NRS-A is sitting with the plantar surface of the ball of the surgically attended foot touching the floor (no weight bearing). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 72 Hours Postsurgery (AUC0-72), Compared With Bupivacaine HCl. | 72 hours | Pain intensity is assessed 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. The prescribed activity for NRS-A is sitting with the plantar surface of the ball of the surgically attended foot touching the floor (no weight bearing). |
| Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Saline Placebo. | 72 hours | — |
| Percentage of Subjects Who Are Opioid-free for HTX-011 Compared With Bupivacaine HCl. | 72 hours | — |
| Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Bupivacaine HCl. | 72 hours | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group 1: HTX-011 HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation. | 157 |
| Treatment Group 2: Saline Placebo Saline placebo by instillation. | 100 |
| Treatment Group 3: Bupivacaine HCI Bupivacaine HCl without epinephrine, 50 mg by injection. | 155 |
| Total | 412 |
Baseline characteristics
| Characteristic | Treatment Group 1: HTX-011 | Treatment Group 2: Saline Placebo | Treatment Group 3: Bupivacaine HCI | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 8 Participants | 16 Participants | 48 Participants |
| Age, Categorical Between 18 and 65 years | 133 Participants | 92 Participants | 139 Participants | 364 Participants |
| Age, Continuous | 48.0 years STANDARD_DEVIATION 14.47 | 47.3 years STANDARD_DEVIATION 12.83 | 45.5 years STANDARD_DEVIATION 14.79 | 46.9 years STANDARD_DEVIATION 14.22 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 47 Participants | 32 Participants | 49 Participants | 128 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 110 Participants | 68 Participants | 106 Participants | 284 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 2 Participants | 1 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 24 Participants | 12 Participants | 22 Participants | 58 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 123 Participants | 86 Participants | 128 Participants | 337 Participants |
| Region of Enrollment United States | 157 participants | 100 participants | 155 participants | 412 participants |
| Sex: Female, Male Female | 138 Participants | 86 Participants | 132 Participants | 356 Participants |
| Sex: Female, Male Male | 19 Participants | 14 Participants | 23 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 157 | 0 / 101 | 1 / 154 |
| other Total, other adverse events | 111 / 157 | 70 / 101 | 112 / 154 |
| serious Total, serious adverse events | 3 / 157 | 1 / 101 | 3 / 154 |
Outcome results
Primary
Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 72 Hours Postsurgery (AUC0-72), Compared With Saline Placebo.
Pain intensity is assessed 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. The prescribed activity for NRS-A is sitting with the plantar surface of the ball of the surgically attended foot touching the floor (no weight bearing).
Time frame: 72 hours
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group 1: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 72 Hours Postsurgery (AUC0-72), Compared With Saline Placebo. | 323.29 pain intensity score*hr | Standard Deviation 182.641 |
| Treatment Group 2: Saline Placebo | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 72 Hours Postsurgery (AUC0-72), Compared With Saline Placebo. | 445.34 pain intensity score*hr | Standard Deviation 155.792 |
p-value: <0.000195% CI: [-163.76, -80.34]ANOVA
Secondary
Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 72 Hours Postsurgery (AUC0-72), Compared With Bupivacaine HCl.
Pain intensity is assessed 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. The prescribed activity for NRS-A is sitting with the plantar surface of the ball of the surgically attended foot touching the floor (no weight bearing).
Time frame: 72 hours
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group 1: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 72 Hours Postsurgery (AUC0-72), Compared With Bupivacaine HCl. | 323.29 pain intensity score*hr | Standard Deviation 182.641 |
| Treatment Group 2: Saline Placebo | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 72 Hours Postsurgery (AUC0-72), Compared With Bupivacaine HCl. | 393.45 pain intensity score*hr | Standard Deviation 153.756 |
p-value: =0.000295% CI: [-107.07, -33.25]ANOVA
Secondary
Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Bupivacaine HCl.
Time frame: 72 hours
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group 1: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Bupivacaine HCl. | 18.80 IV milligram morphine equivalent (MME) | Standard Deviation 19.801 |
| Treatment Group 2: Saline Placebo | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Bupivacaine HCl. | 25.09 IV milligram morphine equivalent (MME) | Standard Deviation 21.553 |
p-value: =0.0022Wilcoxon (Mann-Whitney)
Secondary
Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Saline Placebo.
Time frame: 72 hours
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group 1: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Saline Placebo. | 18.80 IV milligram morphine equivalent (MME) | Standard Deviation 19.801 |
| Treatment Group 2: Saline Placebo | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Saline Placebo. | 30.06 IV milligram morphine equivalent (MME) | Standard Deviation 21.016 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Percentage of Subjects Who Are Opioid-free for HTX-011 Compared With Bupivacaine HCl.
Time frame: 72 hours
Population: ITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group 1: HTX-011 | Percentage of Subjects Who Are Opioid-free for HTX-011 Compared With Bupivacaine HCl. | 45 Participants |
| Treatment Group 2: Saline Placebo | Percentage of Subjects Who Are Opioid-free for HTX-011 Compared With Bupivacaine HCl. | 17 Participants |
p-value: 0.000195% CI: [0.085, 0.265]Fisher Exact