Postoperative Pain
Conditions
Brief summary
A Phase 2, Randomized, Pilot Study to Investigate the Safety, Efficacy, Pharmacokinetics and Bioavailability of HTX-011, HTX-002, or HTX-009 Administered Via Injection and/or Topical Application Following Unilateral Open Inguinal Herniorrhaphy
Detailed description
This study includes multiple formulations for formulation selection of the fixed-combination product and for the factorial design assessment of the contribution of each component. HTX-011 is the initial formulation studied (HTX-011-19). HTX-011A is the second formulation studied (HTX-011-49). HTX-011B is the final formulation studied (HTX-011-56), which was also included in subsequent Phase 2b and Phase 3 studies. For the factorial design assessment, HTX-002, a bupivacaine-only formulation in the same HTX-011 proprietary polymer, and HTX-009, a meloxicam-only formulation in the same HTX-011 proprietary polymer, were evaluated.
Interventions
DRUGHTX-011
HTX-011 (bupivacaine/meloxicam) by injection.
DRUGPlacebo
Saline placebo by injection.
DRUGHTX-002
HTX-002, by injection or instillation (pooled).
DRUGBupivacaine HCI (Marcaine)
Bupivacaine HCI (Marcaine) by injection.
DRUGHTX-011A
HTX-011A (bupivacaine/meloxicam) by injection.
DRUGHTX-011B
HTX-011B (bupivacaine/meloxicam) by injection, instillation or combination.
DRUGHTX-009
HTX-009 by injection and instillation (combination).
Sponsors
Heron Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Be male or female 18 years of age or older. 2. Female subjects are eligible only if all of the following apply: Not pregnant (female subject of child bearing potential must have a negative serum pregnancy test at screening and negative urine pregnancy test before surgery) * Not lactating * Not planning to become pregnant during the study * Be surgically sterile; or at least two years post-menopausal; or have a monogamous partner who is surgically sterile; or is practicing double-barrier contraception; or practicing abstinence (must agree to use double-barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, or combination oral contraceptive approved by the FDA for greater than 2 months prior to screening visits and commits to the use of an acceptable form of birth control for the duration of the study and for 30 days from completion of the study Male: o Must be surgically sterile (biologically or surgically) or commit to the use of a reliable method of birth control for the duration of the study until at least 1 week after the administration of study medication. 3. Plan to undergo a unilateral inguinal herniorrhaphy 4. Have the ability and be willing to comply with the study procedures 5. Must be able to understand study procedures and give informed consent for the conduct for all study procedures, using an IRB approved consent form.
Exclusion criteria
1. Unwilling to sign informed consent or not willing or able to complete all study procedures 2. Have a contraindication or be allergic to any medication to be used during the trial period 3. Have clinically significant cardiac abnormalities, that in the opinion of the investigator would pose a health risk to the subject should they participate in the trial 4. Have American Society of Anesthesiologists (ASA) Physical Status classification system category 4 or greater (Appendix E) 5. Have clinically significant renal or hepatic abnormalities (defined as an AST or ALT \> 3x ULN, creatinine \> 2x ULN) 6. Have another painful condition that may confound pain assessments 7. Have another surgery planned within 30 days of procedure, or presents with bilateral or recurrent inguinal hernia, other hernia presentations, or hernias with large scrotal component that would be difficult to reduce surgically 8. Have a known or suspected history of alcohol or drug abuse, or a positive drug screen 9. Currently taking analgesics for a chronically painful condition, or has taken long acting opioids within 3 days of surgery, or taken any opioids within 24 hours of surgery 10. Subjects with documented sleep apnea or are on home continuous positive airway pressure (CPAP) 11. Female subjects who are pregnant (positive pregnancy test at screening or on the day of surgery) 12. Subjects who are receiving oxygen therapy at the time of screening 13. Have participated in a clinical trial within 30 days of planned surgery 14. Have a body mass index (BMI) \> 39 kg/m2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Summed Pain Intensity (SPI) Score | 24 hours | Subjects assessed pain intensity for their current pain with the 11-point (0 to 10) Numeric Rating Scale NRS where "0" equated to "no pain" and "10" equated to "the worst pain imaginable". Pain intensity was assessed at rest (NRS-R) after the subject had been supine for a minimum of 5 minutes and with activity (NRS-A) sitting up from a supine position. The SPI is derived by summing the pain intensity score weighted by the scheduled time duration. SPI0-24 was calculated by summing the Pain intensity (PI) score at the relevant time points weighted by the scheduled time duration since the prior PI assessment as follows: SPI0-24= PI1+PI2+2\*PI4+2\*PI6+2\*PI8+2\*PI10+2\*PI12+2\*PI14+4\*PI18+6\*PI24. Min = 0 (if PI=0 at every time) and Max = 240 (if PI=10 at every time). |
Countries
United States
Participant flow
Pre-assignment details
Study HTX-011-202 included multiple study parts, various study drugs, formulations, and administration techniques. It was pre-specified in the SAP to pool different doses of the same study drug within study parts for Participant Flow, Baseline Characteristics, and AEs. We pooled different doses of the same study drug within study parts for Participant Flow, Baseline Characteristics, and AEs. However for Outcome Measures, different doses of study drugs were presented separately.
Participants by arm
| Arm | Count |
|---|---|
| Part A, Cohorts A, B C, D, E: HTX-011 HTX-011 (bupivacaine/meloxicam), 200-400 mg/6-12 mg by injection, instillation or combination (pooled). | 89 |
| Part A, Cohort F: Saline Placebo Saline placebo by injection. | 18 |
| Part B/C/D/E/F/G: HTX-011A HTX-011A (bupivacaine/meloxicam), 200-400 mg/6-12 mg by injection. | 39 |
| Parts B/C/D/E/F/G: HTX-002 HTX-002, 200-400 mg by injection or instillation (pooled). | 51 |
| Parts B/C/D/E/F/G: HTX-011B HTX-011B (bupivacaine/meloxicam), 200-400 mg/6-12 mg by injection, instillation or combination (pooled). | 131 |
| Parts B/C/D/E/F/G: HTX-009 HTX-009, 12 mg by injection and instillation (combination). | 18 |
| Parts B/C/D/E/F/G: Bupivacaine (Marcaine Bupivacaine HCI, 75 mg by injection. | 32 |
| Parts A/B/C/D/E/F/G: Saline Placebo Saline placebo by injection. | 85 |
| Total | 463 |
Baseline characteristics
| Characteristic | Part A, Cohorts A, B C, D, E: HTX-011 | Total | Parts A/B/C/D/E/F/G: Saline Placebo | Parts B/C/D/E/F/G: Bupivacaine (Marcaine | Parts B/C/D/E/F/G: HTX-009 | Parts B/C/D/E/F/G: HTX-011B | Parts B/C/D/E/F/G: HTX-002 | Part B/C/D/E/F/G: HTX-011A | Part A, Cohort F: Saline Placebo |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 45.4 years STANDARD_DEVIATION 12.56 | 46.1 years STANDARD_DEVIATION 12.82 | 46.0 years STANDARD_DEVIATION 12.4 | 41.7 years STANDARD_DEVIATION 12.74 | 49.8 years STANDARD_DEVIATION 10.73 | 45.6 years STANDARD_DEVIATION 13.3 | 46.8 years STANDARD_DEVIATION 14.26 | 50.8 years STANDARD_DEVIATION 9.99 | 46.5 years STANDARD_DEVIATION 13.99 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 42 Participants | 191 Participants | 36 Participants | 11 Participants | 4 Participants | 57 Participants | 21 Participants | 13 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 272 Participants | 49 Participants | 21 Participants | 14 Participants | 74 Participants | 30 Participants | 26 Participants | 11 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 | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 6 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 57 Participants | 14 Participants | 4 Participants | 4 Participants | 11 Participants | 6 Participants | 6 Participants | 0 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 | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 77 Participants | 395 Participants | 70 Participants | 27 Participants | 13 Participants | 112 Participants | 45 Participants | 33 Participants | 18 Participants |
| Region of Enrollment United States | 89 participants | 463 participants | 85 participants | 32 participants | 18 participants | 131 participants | 51 participants | 39 participants | 18 participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 84 Participants | 451 Participants | 84 Participants | 31 Participants | 17 Participants | 129 Participants | 49 Participants | 39 Participants | 18 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 / 89 | 0 / 18 | 0 / 39 | 0 / 51 | 0 / 131 | 0 / 18 | 0 / 32 | 0 / 85 |
| other Total, other adverse events | 56 / 89 | 13 / 18 | 20 / 39 | 28 / 51 | 85 / 131 | 13 / 18 | 19 / 32 | 52 / 85 |
| serious Total, serious adverse events | 1 / 89 | 1 / 18 | 0 / 39 | 0 / 51 | 2 / 131 | 2 / 18 | 1 / 32 | 1 / 85 |
Outcome results
Primary
Mean Summed Pain Intensity (SPI) Score.
The SPI is derived by summing the pain intensity score weighted by the scheduled time duration. SPI0-24 will be calculated by summing the Pain intensity (PI) score at the relevant time points weighted by the scheduled time duration since the prior PI assessment as follows: SPI0-24= PI1+PI2+2\*PI4+2\*PI6+2\*PI8+2\*PI10+2\*PI12+2\*PI14+4\*PI18+6\*PI24. Min = 0 (if PI=0 at every time) and Max = 240 (if PI=10 at every time).
Time frame: 24 hours
Population: mITT Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HTX-011: 200 mg | Mean Summed Pain Intensity (SPI) Score. | 83.71 Units on a scale | Standard Deviation 45.996 |
| HTX-011: 400 mg | Mean Summed Pain Intensity (SPI) Score. | 77.63 Units on a scale | Standard Deviation 40.679 |
| HTX-011A: 200 mg | Mean Summed Pain Intensity (SPI) Score. | 95.24 Units on a scale | Standard Deviation 50.135 |
| HTX-011A: 400 mg | Mean Summed Pain Intensity (SPI) Score. | 89.28 Units on a scale | Standard Deviation 59.403 |
| HTX-011B: 200 mg | Mean Summed Pain Intensity (SPI) Score. | 97.16 Units on a scale | Standard Deviation 49.093 |
| HTX-011B: 300 mg | Mean Summed Pain Intensity (SPI) Score. | 73.81 Units on a scale | Standard Deviation 50.572 |
| HTX-011B: 400 mg | Mean Summed Pain Intensity (SPI) Score. | 86.61 Units on a scale | Standard Deviation 40.091 |
| HTX-002: 200 mg | Mean Summed Pain Intensity (SPI) Score. | 99.82 Units on a scale | Standard Deviation 41.433 |
| HTX-002: 400 mg | Mean Summed Pain Intensity (SPI) Score. | 99.53 Units on a scale | Standard Deviation 45.415 |
| HTX-009: 12 mg | Mean Summed Pain Intensity (SPI) Score. | 118.22 Units on a scale | Standard Deviation 26.399 |
| Saline Placebo | Mean Summed Pain Intensity (SPI) Score. | 121.93 Units on a scale | Standard Deviation 48.239 |
| Bupivacaine HCI | Mean Summed Pain Intensity (SPI) Score. | 108.72 Units on a scale | Standard Deviation 37.552 |