Postsurgical Pain
Conditions
Brief summary
Phase 2, single center, randomized, double-blind, placebo-controlled, parallel design study of CA-008 vs. placebo in subjects undergoing an elective C-ABD under general anesthesia supplemented with a bupivacaine hydrochloride (HCl)transverse abdominis plane (TAP) block.
Detailed description
This is a Phase 2, single-center, randomized, double-blind, placebo-controlled, parallel design study evaluating up to 4 ascending dose level cohorts, each evaluating a single dose of CA-008 vs. placebo injected/instilled during an elective C-ABD. Up to 72 subjects may be randomized in 4 cohorts. For each subject, postsurgical assessments will be conducted in two parts: * Inpatient period: starts with completion of study treatment injection (T0) and continues through 96 hours (T96h). * Outpatient period: begins on discharge from the inpatient unit through various follow up visits to day 29 (D29)/week 4 (W4) after surgery. Note that additional follow up visits may occur at any time or even after D29/W4 to follow adverse events (AEs) to resolution or establishment of a new baseline.
Interventions
DRUGCA-008 5 mg
5 mg CA-008 reconstituted in saline.
DRUGPlacebo
Each cohort will use placebo reconstituted in saline.
DRUGBupivacaine Hydrochloride
0.25% administered pre-surgery
DRUGHydromorphone
0.02 mg/kg IV administered intraoperatively
DRUGFentanyl
100 mcg IV administered intraoperatively
DRUGAcetaminophen
1000 mg IV administered intraoperatively
DRUGOxycodone
5-10 mg PO administered post-surgery
DRUGCA-008 10 mg
10 mg CA-008 reconstituted in saline.
DRUGCA-008 15 mg
15 mg CA-008 reconstituted in saline.
Sponsors
Concentric Analgesics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Plan to undergo an elective complete abdominoplasty (C-ABD), without collateral procedure or additional surgeries. * In the medical judgment of the investigator, be a reasonably healthy adult aged 18 - 65 years old, inclusive, and American Society of Anesthesiology (ASA) physical Class 1 or 2 at the time of randomization. * Unless the subject has a same sex partner, he or she must either be sterile (surgically or biologically) or commit to an acceptable method of birth control while participating in the study. * Have a body mass index ≤ 35 kg/m². * Be willing and able to sign the informed consent form (ICF) approved by an Institutional Review Board (IRB). Key
Exclusion criteria
* In the opinion of the Investigator, have a concurrent painful condition that may require analgesic treatment during the study period or may confound post-surgical pain assessments. * Have a known allergy to chili peppers, capsaicin or the components of CA-008, acetaminophen, bupivacaine, fentanyl hydromorphone or oxycodone. * As determined by the investigator have a history or clinical manifestation of significant medical, neuropsychiatric or other condition, including a clinically significant existing arrhythmia, left bundle branch block or abnormal ECG, myocardial infarction or coronary arterial bypass graft surgery within the prior 12 months, significant abnormal clinical laboratory test value, or known bleeding abnormality that could preclude or impair study participation or interfere with study assessments. * The following are considered disallowed medications: 1. Be tolerant to opioids defined as those who have been receiving or have received chronic opioid therapy greater than 15 mg of oral morphine equivalents per day for greater than 3 out of 7 days per week over a one-month period within 6 months of screening. 2. Within 1 day prior to surgery and throughout the inpatient period, be taking any capsaicin-containing products, such as dietary supplements or over-the-counter (OTC) preparations, including topical formulations, and prescription medications. 3. Within the 7 days prior to surgery, be taking any central nervous system (CNS) active agent as an analgesic adjunct medication, such as anticonvulsants, antidepressants, benzodiazepines, sedative- hypnotics, clonidine and other central alpha-2 agents, ketamine or muscle relaxants. i. These drugs are permitted if prescribed for non-pain indications and the dose has been stable for at least 30 days prior to surgery. ii. The use of benzodiazepines and the non-benzodiazepines are permitted to treat insomnia during the postoperative period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Intensity Scores at 96 Hours at Rest Using Numerical Rating Scale (NRS) | 96 hours | Numeric Rating Scale (NRS) of pain intensity from 0-10 where 0 is no pain and 10 is the worst pain imaginable at 96 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Opioid Cessation or Freedom | From Surgery to Day 29 | Time to the last use of opioid |
| Weighted Sum of Pain Intensity (SPI) Assessments = AUC of NRS Scores | 0 to 96 hours | Pain intensity scores (using a Numeric Rating Scale of pain intensity from 0-10 where 0 is no pain and 10 is the worst pain imaginable) from 0 to T96 hours |
| Percent of Opioid Free Subjects | 24 to 96 hours | Percent of subjects who were opioid free at 24-96 hours |
| Total Opioid Consumption | 0 to 96 hours | The sum of daily opioid consumption (in morphine equivalents) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 Cohort 1 (CA-008 5 mg): the surgery for each subject is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg).
CA-008 5 mg: 5 mg CA-008
Bupivacaine Hydrochloride: 0.25% administered pre-surgery
Hydromorphone: 0.02 mg/kg IV administered intraoperatively
Fentanyl: 100 mcg IV administered intraoperatively
Acetaminophen: 1000 mg IV administered intraoperatively
Oxycodone: 5-10 mg PO administered post-surgery | 9 |
| Placebo for Cohort 1 Cohort 1:
Placebo comparator is identical in appearance to the investigational product, containing the same excipients as the active.
The surgery for each subject is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg).
Placebo: Each cohort will use placebo reconstituted in saline.
Bupivacaine Hydrochloride: 0.25% administered pre-surgery
Hydromorphone: 0.02 mg/kg IV administered intraoperatively
Fentanyl: 100 mcg IV administered intraoperatively
Acetaminophen: 1000 mg IV administered intraoperatively
Oxycodone: 5-10 mg PO administered post-surgery | 9 |
| CA-008 10 mg (0.1 mg/mL) Cohort 2 (CA-008 10 mg): the surgery is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg).
Bupivacaine Hydrochloride: 0.25% administered pre-surgery
Hydromorphone: 0.02 mg/kg IV administered intraoperatively
Fentanyl: 100 mcg IV administered intraoperatively
Acetaminophen: 1000 mg IV administered intraoperatively
Oxycodone: 5-10 mg PO administered post-surgery
CA-008 10 mg: 10 mg CA-008 | 12 |
| CA-008 15 mg (0.15 mg/mL) Cohort 3 (CA-008 15 mg): the surgery is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg).
Bupivacaine Hydrochloride: 0.25% administered pre-surgery
Hydromorphone: 0.02 mg/kg IV administered intraoperatively
Fentanyl: 100 mcg IV administered intraoperatively
Acetaminophen: 1000 mg IV administered intraoperatively
Oxycodone: 5-10 mg PO administered post-surgery
CA-008 15 mg: 15 mg CA-008 | 12 |
| Placebo for Cohorts 2 and 3 Cohorts 2 & 3:
Placebo comparator in each cohort is identical in appearance to the investigational product, containing the same excipients as the active.
The surgery for each subject is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg).
Placebo: Each cohort will use placebo reconstituted in saline.
Bupivacaine Hydrochloride: 0.25% administered pre-surgery
Hydromorphone: 0.02 mg/kg IV administered intraoperatively
Fentanyl: 100 mcg IV administered intraoperatively
Acetaminophen: 1000 mg IV administered intraoperatively
Oxycodone: 5-10 mg PO administered post-surgery | 12 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | CA-008 5 mg (0.05 mg/mL) Cohort 1 | Total | Placebo for Cohorts 2 and 3 | CA-008 15 mg (0.15 mg/mL) | CA-008 10 mg (0.1 mg/mL) | Placebo for Cohort 1 |
|---|---|---|---|---|---|---|
| Age, Continuous | 37.8 years STANDARD_DEVIATION 10.95 | 40.4 years STANDARD_DEVIATION 8.93 | 38.3 years STANDARD_DEVIATION 8.76 | 43.3 years STANDARD_DEVIATION 6.74 | 43.3 years STANDARD_DEVIATION 10.27 | 38.2 years STANDARD_DEVIATION 7.17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 25 Participants | 4 Participants | 6 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 29 Participants | 8 Participants | 6 Participants | 8 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 17 Participants | 6 Participants | 3 Participants | 6 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 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 |
| Race (NIH/OMB) White | 7 Participants | 33 Participants | 5 Participants | 8 Participants | 5 Participants | 8 Participants |
| Region of Enrollment United States | 9 Participants | 54 Participants | 12 Participants | 12 Participants | 12 Participants | 9 Participants |
| Sex: Female, Male Female | 9 Participants | 54 Participants | 12 Participants | 12 Participants | 12 Participants | 9 Participants |
| Sex: Female, Male Male | 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 9 / 9 | 8 / 9 | 11 / 12 | 10 / 12 | 11 / 12 |
| serious Total, serious adverse events | 2 / 9 | 0 / 9 | 1 / 12 | 1 / 12 | 0 / 12 |
Outcome results
Primary
Pain Intensity Scores at 96 Hours at Rest Using Numerical Rating Scale (NRS)
Numeric Rating Scale (NRS) of pain intensity from 0-10 where 0 is no pain and 10 is the worst pain imaginable at 96 hours
Time frame: 96 hours
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 | Pain Intensity Scores at 96 Hours at Rest Using Numerical Rating Scale (NRS) | 2.8 score on a scale | Standard Deviation 2.59 |
| Placebo for Cohort 1 | Pain Intensity Scores at 96 Hours at Rest Using Numerical Rating Scale (NRS) | 2.0 score on a scale | Standard Deviation 2.12 |
| CA-008 10 mg (0.1 mg/mL) | Pain Intensity Scores at 96 Hours at Rest Using Numerical Rating Scale (NRS) | 3.0 score on a scale | Standard Deviation 2.22 |
| CA-008 15 mg (0.15 mg/mL) | Pain Intensity Scores at 96 Hours at Rest Using Numerical Rating Scale (NRS) | 2.8 score on a scale | Standard Deviation 3.1 |
| Placebo for Cohorts 2 and 3 | Pain Intensity Scores at 96 Hours at Rest Using Numerical Rating Scale (NRS) | 1.8 score on a scale | Standard Deviation 1.96 |
p-value: 0.2912ANOVA
Secondary
Percent of Opioid Free Subjects
Percent of subjects who were opioid free at 24-96 hours
Time frame: 24 to 96 hours
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 | Percent of Opioid Free Subjects | 0 Participants |
| Placebo for Cohort 1 | Percent of Opioid Free Subjects | 0 Participants |
| CA-008 10 mg (0.1 mg/mL) | Percent of Opioid Free Subjects | 1 Participants |
| CA-008 15 mg (0.15 mg/mL) | Percent of Opioid Free Subjects | 1 Participants |
| Placebo for Cohorts 2 and 3 | Percent of Opioid Free Subjects | 0 Participants |
p-value: 0.9546Regression, Logistic
Secondary
Time to Opioid Cessation or Freedom
Time to the last use of opioid
Time frame: From Surgery to Day 29
Population: Safety population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 | Time to Opioid Cessation or Freedom | 56.37 hours |
| Placebo for Cohort 1 | Time to Opioid Cessation or Freedom | 55.42 hours |
| CA-008 10 mg (0.1 mg/mL) | Time to Opioid Cessation or Freedom | 83.89 hours |
| CA-008 15 mg (0.15 mg/mL) | Time to Opioid Cessation or Freedom | 59.55 hours |
| Placebo for Cohorts 2 and 3 | Time to Opioid Cessation or Freedom | 42.26 hours |
p-value: 0.1958Log Rank
Secondary
Total Opioid Consumption
The sum of daily opioid consumption (in morphine equivalents)
Time frame: 0 to 96 hours
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 | Total Opioid Consumption | 85.83 mg morphine equivalents | Standard Deviation 52.246 |
| Placebo for Cohort 1 | Total Opioid Consumption | 96.67 mg morphine equivalents | Standard Deviation 63.134 |
| CA-008 10 mg (0.1 mg/mL) | Total Opioid Consumption | 69.77 mg morphine equivalents | Standard Deviation 41.71 |
| CA-008 15 mg (0.15 mg/mL) | Total Opioid Consumption | 58.00 mg morphine equivalents | Standard Deviation 69.17 |
| Placebo for Cohorts 2 and 3 | Total Opioid Consumption | 77.85 mg morphine equivalents | Standard Deviation 72.524 |
p-value: 0.4434ANOVA
Secondary
Weighted Sum of Pain Intensity (SPI) Assessments = AUC of NRS Scores
Pain intensity scores (using a Numeric Rating Scale of pain intensity from 0-10 where 0 is no pain and 10 is the worst pain imaginable) from 0 to T96 hours
Time frame: 0 to 96 hours
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 | Weighted Sum of Pain Intensity (SPI) Assessments = AUC of NRS Scores | 392.98 score on a scale*hours | Standard Deviation 138.191 |
| Placebo for Cohort 1 | Weighted Sum of Pain Intensity (SPI) Assessments = AUC of NRS Scores | 392.67 score on a scale*hours | Standard Deviation 163.025 |
| CA-008 10 mg (0.1 mg/mL) | Weighted Sum of Pain Intensity (SPI) Assessments = AUC of NRS Scores | 384.94 score on a scale*hours | Standard Deviation 136.551 |
| CA-008 15 mg (0.15 mg/mL) | Weighted Sum of Pain Intensity (SPI) Assessments = AUC of NRS Scores | 406.88 score on a scale*hours | Standard Deviation 220.821 |
| Placebo for Cohorts 2 and 3 | Weighted Sum of Pain Intensity (SPI) Assessments = AUC of NRS Scores | 356.23 score on a scale*hours | Standard Deviation 175.969 |
p-value: 0.498ANOVA