Postoperative Pain
Conditions
Brief summary
This is a Phase 2B, randomized, assessor-blind, active- and saline placebo-controlled, multicenter study in subjects undergoing augmentation mammoplasty to evaluate the analgesic efficacy, safety, and pharmacokinetics (PK) of HTX-011 when administered via ultrasound-guided lateral and medial pectoral nerve block before surgery.
Interventions
DRUGHTX-011
HTX-011 (bupivacaine/meloxicam) via nerve block or instillation.
DRUGBupivacaine HCl without epinephrine
Bupivacaine HCl without epinephrine, 50 mg via nerve block.
DRUGSaline Placebo
Saline placebo via nerve block.
Sponsors
Heron Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Is scheduled to undergo primary bilateral submuscular augmentation mammoplasty with saline or silicone smooth implants with a volume of 300 to 500 cc, inclusive. Note: textured implants are not allowed. * Has an American Society of Anesthesiologists Physical Status of I, II, or III. * 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. * Has a planned reconstructive procedure status post breast cancer therapy. * Has a 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 medication. * 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 scheduled surgery. * Has been administered bupivacaine within 5 days prior to the scheduled surgery. * Has been administered any local anesthetic within 72 hours prior to the scheduled surgery other than to treat an AE that occurs after signing the ICF or for pretreatment prior to a needle placement. * Has initiated treatment with any of the following medications within 1 month prior to study drug administration or is taking any of these medications to control pain: selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin, duloxetine, or cyclooxygenase-2 (COX-2) inhibitors. (Note: If a subject is taking one of these medications for a reason other than pain control, she must be on a stable scheduled dose \[ie, not "as needed"\] for at least 1 month prior to study drug administration.) Anxiolytics prior to surgery are permitted, if necessary. * Has a medical condition 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, Hepatitis C, or human immunodeficiency virus (HIV). * Has uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments * Has any chronic neuromuscular deficit of either pectoral nerve function or arm/shoulder/truncal 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. 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 in 12 months. * Has a body mass index (BMI) \>35 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 24 Hours Postsurgery (AUC0-24). | 24 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 AUC0-24 is 0-240. The prescribed activity for NRS-A is keeping the elbows at the side and against the body and then raising both hands in front of the abdomen with hands clasped and holding that position for at least 5 seconds. |
Secondary
| Measure | Time frame |
|---|---|
| Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 72 Hours |
Countries
United States
Participant flow
Pre-assignment details
A total of 243 subjects received study drug.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: HTX-011 HTX-011 (bupivacaine/meloxicam), 60 mg/1.8 mg via nerve block | 12 |
| Group 2: HTX-011 HTX-011(bupivacaine/meloxicam), 120 mg/3.6 mg via nerve block | 27 |
| Group 3: HTX-011 HTX-011(bupivacaine/meloxicam), 240 mg/7.2 mg via nerve block | 25 |
| Group 4: HTX-011 HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg via nerve block | 47 |
| Group 5: HTX-011 HTX-011 (bupivacaine/meloxicam), 400 mg/ 12 mg via instillation | 50 |
| Group 6: Bupivacaine HCl Bupivacaine HCl without epinephrine, 50 mg via nerve block | 41 |
| Group 7: Saline Placebo Saline placebo via nerve block | 41 |
| Total | 243 |
Baseline characteristics
| Characteristic | Group 1: HTX-011 | Total | Group 7: Saline Placebo | Group 6: Bupivacaine HCl | Group 5: HTX-011 | Group 4: HTX-011 | Group 3: HTX-011 | Group 2: HTX-011 |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 243 Participants | 41 Participants | 41 Participants | 50 Participants | 47 Participants | 25 Participants | 27 Participants |
| Age, Continuous | 31.4 Years STANDARD_DEVIATION 6.56 | 31.2 Years STANDARD_DEVIATION 8.01 | 31.3 Years STANDARD_DEVIATION 9.03 | 30.4 Years STANDARD_DEVIATION 7.75 | 32.0 Years STANDARD_DEVIATION 8.64 | 30.9 Years STANDARD_DEVIATION 8.08 | 30.5 Years STANDARD_DEVIATION 5.64 | 32.1 Years STANDARD_DEVIATION 8.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 94 Participants | 16 Participants | 17 Participants | 17 Participants | 18 Participants | 10 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 149 Participants | 25 Participants | 24 Participants | 33 Participants | 29 Participants | 15 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 11 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 36 Participants | 7 Participants | 3 Participants | 11 Participants | 6 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 194 Participants | 32 Participants | 35 Participants | 37 Participants | 38 Participants | 20 Participants | 22 Participants |
| Region of Enrollment United States | 12 participants | 243 participants | 41 participants | 41 participants | 50 participants | 47 participants | 25 participants | 27 participants |
| Sex: Female, Male Female | 12 Participants | 243 Participants | 41 Participants | 41 Participants | 50 Participants | 47 Participants | 25 Participants | 27 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 27 | 0 / 25 | 0 / 47 | 0 / 50 | 0 / 41 | 0 / 41 |
| other Total, other adverse events | 11 / 12 | 21 / 27 | 23 / 25 | 43 / 47 | 47 / 50 | 33 / 41 | 35 / 41 |
| serious Total, serious adverse events | 0 / 12 | 0 / 27 | 1 / 25 | 0 / 47 | 1 / 50 | 2 / 41 | 0 / 41 |
Outcome results
Primary
Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 24 Hours Postsurgery (AUC0-24).
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 AUC0-24 is 0-240. The prescribed activity for NRS-A is keeping the elbows at the side and against the body and then raising both hands in front of the abdomen with hands clasped and holding that position for at least 5 seconds.
Time frame: 24 hours
Population: mITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 24 Hours Postsurgery (AUC0-24). | 124.51 pain intensity score*hr | Standard Deviation 59.462 |
| Group 2: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 24 Hours Postsurgery (AUC0-24). | 136.17 pain intensity score*hr | Standard Deviation 58.598 |
| Group 3: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 24 Hours Postsurgery (AUC0-24). | 136.76 pain intensity score*hr | Standard Deviation 56.034 |
| Group 4: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 24 Hours Postsurgery (AUC0-24). | 116.71 pain intensity score*hr | Standard Deviation 52.622 |
| Group 5: HTX-011 | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 24 Hours Postsurgery (AUC0-24). | 114.87 pain intensity score*hr | Standard Deviation 48.214 |
| Group 6: Bupivacaine HCl | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 24 Hours Postsurgery (AUC0-24). | 133.83 pain intensity score*hr | Standard Deviation 49.493 |
| Group 7: Saline Placebo | Mean Area Under the Curve (AUC) of the Numeric Rating Scale (NRS) Pain Intensity Scores With Activity (NRS-A) Through 24 Hours Postsurgery (AUC0-24). | 151.52 pain intensity score*hr | Standard Deviation 46.213 |
Secondary
Mean Total Postoperative Opioid Consumption (in Morphine Equivalents)
Time frame: 72 Hours
Population: mITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 38.71 Morphine milligram equivalents (MME) | Standard Deviation 28.65 |
| Group 2: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 24.39 Morphine milligram equivalents (MME) | Standard Deviation 19.878 |
| Group 3: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 38.00 Morphine milligram equivalents (MME) | Standard Deviation 19.452 |
| Group 4: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 28.84 Morphine milligram equivalents (MME) | Standard Deviation 22.603 |
| Group 5: HTX-011 | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 37.46 Morphine milligram equivalents (MME) | Standard Deviation 21.452 |
| Group 6: Bupivacaine HCl | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 33.57 Morphine milligram equivalents (MME) | Standard Deviation 23.088 |
| Group 7: Saline Placebo | Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) | 36.38 Morphine milligram equivalents (MME) | Standard Deviation 23.275 |