Bunions, Postoperative Pain
Conditions
Keywords
Analgesia, Bunionectomy
Brief summary
This was a Phase 1b/2, randomized, blinded, active-controlled study. Phase 1b evaluated escalating doses of HTX-034 compared with bupivacaine HCl. Phase 2 was a dose-expansion phase to evaluate additional subjects treated with the HTX-034 dose selected based on Phase 1b, compared with bupivacaine HCl.
Interventions
DRUGHTX-034 low dose
HTX-034 (bupivacaine/aprepitant/meloxicam) fixed dose: 21.7 mg/4.3 mg/0.6 mg
DRUGHTX-034 high dose
HTX-034 (bupivacaine/aprepitant/meloxicam) individualized dose: 30.6 mg/6.1 mg/0.9 mg to 51.5 mg/10.3 mg/1.5 mg
DEVICELuer lock applicator
Applicator for instillation
DRUGBupivacaine HCl
Bupivacaine HCl 50 mg
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 medically fit to undergo an elective unilateral, first metatarsal bunionectomy with osteotomy and internal fixation under regional anesthesia; no neuraxial technique (eg, no spinal, epidural, or general anesthesia). * Has an American Society of Anesthesiologists (ASA) 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
* Had contralateral foot bunionectomy in the past 3 months. * Has a planned concurrent surgical procedure. * Has a contraindication or a known or suspected history of hypersensitivity or clinically significant idiosyncratic reaction to required study medications. * Has a pre-existing concurrent acute or chronic painful physical/restrictive condition expected to require analgesic treatment in the postoperative period for pain. * Has received or is taking a contraindicated or prohibited medications. * Received an investigational product or device in a clinical trial within 30 days or within 5 elimination half lives. * 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. * Has a history of clinically significant cardiac abnormality such as myocardial infarction within 6 months. * Has a history of coronary artery bypass graft surgery within 12 months. * Has a history of known or suspected coagulopathy. * 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 undergone 3 or more surgeries within 12 months. * Has a known history of glucose-6-phosphate dehydrogenase deficiency. * Has any of the following laboratory abnormalities during Screening (1 retest permitted): * Severe liver function impairment. * Severe kidney function impairment. * Platelet count \<100,000/μL, hemoglobin \<12 g/dL, or hematocrit \<35%. * Has a body mass index (BMI) \>39 kg/m2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of TEAEs in Phases 1b/2 | 42 days | The data from Phase 1b and Phase 2 were combined for each treatment group because the dose for bupivacaine HCI, HTX-034 low dose and HTX-034 high dose were the same, in both Phases, respectively. In addition, the surgical procedure, protocol assessments, and participating sites were the same in both Phases. |
| AUC0-72 of Pain Scores | through 72 hours | Mean area under the curve (AUC) of the Numeric Rating Scale (NRS) of pain intensity scores with activity (windowed worst observation carried forward) through 72 hours. The NRS was an 11-point scale (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable". The data from Phase 1b and Phase 2 were combined for each treatment group because the dose for bupivacaine HCI, HTX-034 low dose and HTX-034 high dose were the same, in both Phases, respectively. In addition, the surgical procedure, protocol assessments, and participating sites were the same in both Phases. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax for HTX-034 | 29 days | Maximum plasma concentration |
| Tmax for HTX-034 | 29 days | Time of maximum plasma concentration |
| AUClast for HTX-034 | 29 days | Area under the concentration-time curve from Time 0 to the time of the last quantifiable concentration |
| AUCinf for HTX-034 | 22 days | Area under the concentration-time curve from Time 0 extrapolated to infinity (Phase 1b only) |
| t½ of HTX-034 | 22 days | Apparent terminal half-life of HTX-034 (Phase 1b only) |
| Mean AUC of Pain Scores With Activity | 7 days | Mean AUC of the Numeric Rating Scale (NRS) scores with activity (windowed worst observation carried forward). Pain intensity scores were assessed using an 11-point NRS (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable". The data from Phase 1b and Phase 2 were combined for each treatment group because the dose for bupivacaine HCI, HTX-034 low dose and HTX-034 high dose were the same, in both Phases, respectively. In addition, the surgical procedure, protocol assessments, and participating sites were the same in both Phases. |
| Opioid Consumption | 7 days | Total postoperative opioid consumption (in IV Morphine Milligram Equivalents). The data from Phase 1b and Phase 2 were combined for each treatment group because the dose for bupivacaine HCI, HTX-034 low dose and HTX-034 high dose were the same, in both Phases, respectively. In addition, the surgical procedure, protocol assessments, and participating sites were the same in both Phases. |
| Proportion of Subjects Who Are Opioid-free | After surgery (Day 1) through the Day 15 visit | Proportion of subjects who took no postoperative opioids through Day 15. The data from Phase 1b and Phase 2 were combined for each treatment group because the dose for bupivacaine HCI, HTX-034 low dose and HTX-034 high dose were the same, in both Phases, respectively. In addition, the surgical procedure, protocol assessments, and participating sites were the same in both Phases. |
| Number of Participants With SAEs | 42 days | Number and proportion of subjects with serious adverse events. The data from Phase 1b and Phase 2 were combined for each treatment group because the dose for bupivacaine HCI, HTX-034 low dose and HTX-034 high dose were the same, in both Phases, respectively. In addition, the surgical procedure, protocol assessments, and participating sites were the same in both Phases. |
Countries
United States
Participant flow
Pre-assignment details
The data from Phase 1b and Phase 2 for PD activity and SAEs were combined for each treatment group because the dose for bupivacaine HCI, HTX-034 low dose and HTX-034 high dose were the same, in both Phases, respectively. In addition, the surgical procedure, protocol assessments, and participating sites were the same in both Phases. Pooling across cohorts was pre-specified in the SAP and was used in analysis of the primary efficacy endpoint, as well as in the sample size calculation.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 53.3 years STANDARD_DEVIATION 6.44 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 60 Participants |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 4 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 13 | 0 / 11 | 0 / 21 | 0 / 17 |
| other Total, other adverse events | 8 / 11 | 10 / 13 | 9 / 11 | 13 / 21 | 11 / 17 |
| serious Total, serious adverse events | 0 / 11 | 0 / 13 | 0 / 11 | 0 / 21 | 0 / 17 |
Outcome results
None listed