Postsurgical Pain
Conditions
Brief summary
This is a two-part, Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel design study of CA-008 (vocacapsaicin) vs. placebo injected/instilled during an elective TKA.
Detailed description
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel design study evaluating, in a pilot stage of the study, up to 3 ascending dose level cohorts each evaluating a single dose of CA-008 vs. placebo injected/instilled during an elective TKA. Up to 54 subjects will be randomized in the pilot stage. During the optional second stage of the study, subjects will be randomized to one of either 2 or 3 CA-008 dose levels (to be determined) or placebo. The Sponsor made the decision not to proceed with the second stage.
Interventions
DRUGCA-008
5 mg CA-008 (0.05 mg/mL), 10 mg CA-008 (0.1 mg/mL) and 15 mg CA-008 (0.15 mg/mL)
DRUGPlacebo
Placebo
Sponsors
Concentric Analgesics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Plan to undergo an elective primary unilateral total knee arthroplasty (TKA or knee replacement), without collateral procedure or additional surgeries. 2. Be a reasonably healthy adult aged 18 - 80 years old, inclusive, with a BMI ≤ 36 kg/m2 and American Society of Anesthesiology (ASA) physical Class 1, 2 or 3 at the time of randomization. 3. Males and females must abstain from intercourse, use acceptable birth control methods or be sterile or otherwise incapable of having children. 4. Be willing and able to sign the informed consent form (ICF) 5. Be willing and able to complete study procedures and pain scales and to communicate meaningfully in English. Be able and willing to return for outpatient follow up visits as required. Key
Exclusion criteria
1. In the opinion of the Investigator, 1. have a concurrent painful condition, other than pain in the knee to be replaced, that may require pain treatment during the study period. 2. have active skin disease or other clinically significant abnormality at the anticipated site of surgery that could interfere with the planned surgery. 2. Have a known allergy to chili peppers, capsaicin or the components of CA-008, ropivacaine, ketorolac, acetaminophen, fentanyl, hydromorphone, morphine or oxycodone. 3. Have significant medical, neuropsychiatric or other condition. 4. The following are considered disallowed medications: 1. tolerant to opioids as defined 2. capsaicin-containing products or foods. 3. central nervous system active agent as an analgesic adjunct medication 4. antiarrhythmics except beta-blockers, digoxin, warfarin, lithium, or aminoglycosides or other antibiotics for an infection 5. parenteral or oral corticosteroids. 6. antianginal, antihypertensive agent or diabetic regimen at a dose that has not been stable for at least 30 days or which is not expected to remain stable while participating in the study. 5. Have positive results on the alcohol breath/saliva test indicative of alcohol abuse or urine drug screen indicative of illicit drug use at screening, and/or prior to surgery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-specific Mean Pain Intensity Scores (NRS) at Time 96 Hours for CA-008 vs. Placebo | At 96 hours | Primary Efficacy Endpoint for the Pilot Stage. Time-specific mean pain intensity scores at Time 96 hours for CA-008 vs. placebo based on a 10-point numerical rating scale (NRS) from 0-10 where 0 is no pain and 10 is the worst pain imaginable). |
| CA-008 Dose vs. Placebo Comparison: Area Under the Curve (AUC) 0 to 96 Hours | From 0 hours to 96 hours | Primary Efficacy Endpoint for Stage 2. Area Under the Curve (AUC) of the NRS current pain intensity scores from Time 0 hours to 96 hours at rest (AUC0 to 96h) where 0 is no pain and 10 is the worst pain imaginable for CA-008 compared to placebo. • During the inpatient stay, NRS at rest beginning with the PACU admission may be assessed once the subject is awake. The maximum is an NRS score of 10 x all 96 hours = 960 NRS units\*hrs; the minimum is 0 x 96h = 0 NRS units\*hrs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Who do Not Require Opioids | Time 0 hours to Time 96 hours: Opioid Free 0 hours to 96 hours | Key Secondary Efficacy Endpoints for Stage 2. For each CA-008 dose vs. placebo comparison, percentage of subjects who do not require opioids. |
| Total Opioid Consumption (in Daily Oral Morphine Equivalents) | OC from Time 0 hours to Time 96 hours: OC 0 hours to 96 hours | Key Secondary Efficacy Endpoints for Stage 2. Mean total postoperative opioid consumption (in daily oral morphine equivalents) for CA-008 compared to placebo |
Countries
United States
Participant flow
Recruitment details
One subject in Cohort 3, CA-008 15 mg had an adverse event before receiving treatment and was discontinued from the study without receiving study drug. This subject is not included in the results section
Participants by arm
| Arm | Count |
|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 Cohort 1 (5 mg), was prepared at 0.05 mg/mL CA-008 | 9 |
| Placebo - Cohort 1 Placebo comparator identical in appearance to the investigational product, containing the same excipients as the active | 9 |
| CA-008 10 mg (0.1 mg/mL) Cohort 2 Cohort 2 (10 mg), was prepared at 0.1 mg/mL CA-008 | 13 |
| CA-008 15 mg (0.15 mg/mL) Cohort 3 Cohort 3 (15 mg), was prepared at 0.15 mg/mL CA-008 | 12 |
| Placebo - Cohorts 2 and 3 Placebo comparator identical in appearance to the investigational product, containing the same excipients as the active | 11 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo - Cohort 1 | CA-008 10 mg (0.1 mg/mL) Cohort 2 | CA-008 5 mg (0.05 mg/mL) Cohort 1 | CA-008 15 mg (0.15 mg/mL) Cohort 3 | Placebo - Cohorts 2 and 3 |
|---|---|---|---|---|---|---|
| Age, Continuous | 65.2 years STANDARD_DEVIATION 8 | 61.4 years STANDARD_DEVIATION 7.67 | 66.8 years STANDARD_DEVIATION 7.3 | 64.9 years STANDARD_DEVIATION 9.62 | 67.0 years STANDARD_DEVIATION 8.57 | 64.8 years STANDARD_DEVIATION 7.26 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 7 Participants | 12 Participants | 8 Participants | 10 Participants | 10 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 | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 0 Participants | 4 Participants | 0 Participants | 1 Participants | 2 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 | 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 |
| Race (NIH/OMB) White | 45 Participants | 9 Participants | 9 Participants | 8 Participants | 10 Participants | 9 Participants |
| Region of Enrollment United States | 54 participants | 9 participants | 13 participants | 9 participants | 12 participants | 11 participants |
| Sex: Female, Male Female | 29 Participants | 4 Participants | 8 Participants | 7 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 25 Participants | 5 Participants | 5 Participants | 2 Participants | 6 Participants | 7 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 / 13 | 0 / 12 | 0 / 11 |
| other Total, other adverse events | 7 / 9 | 7 / 9 | 12 / 13 | 10 / 12 | 9 / 11 |
| serious Total, serious adverse events | 1 / 9 | 0 / 9 | 0 / 13 | 1 / 12 | 1 / 11 |
Outcome results
Primary
CA-008 Dose vs. Placebo Comparison: Area Under the Curve (AUC) 0 to 96 Hours
Primary Efficacy Endpoint for Stage 2. Area Under the Curve (AUC) of the NRS current pain intensity scores from Time 0 hours to 96 hours at rest (AUC0 to 96h) where 0 is no pain and 10 is the worst pain imaginable for CA-008 compared to placebo. • During the inpatient stay, NRS at rest beginning with the PACU admission may be assessed once the subject is awake. The maximum is an NRS score of 10 x all 96 hours = 960 NRS units\*hrs; the minimum is 0 x 96h = 0 NRS units\*hrs
Time frame: From 0 hours to 96 hours
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 | CA-008 Dose vs. Placebo Comparison: Area Under the Curve (AUC) 0 to 96 Hours | 476.13 NRS units*hours | Standard Deviation 182.315 |
| Placebo - Cohort 1 | CA-008 Dose vs. Placebo Comparison: Area Under the Curve (AUC) 0 to 96 Hours | 593.93 NRS units*hours | Standard Deviation 178.958 |
| CA-008 10 mg (0.1 mg/mL) Cohort 2 | CA-008 Dose vs. Placebo Comparison: Area Under the Curve (AUC) 0 to 96 Hours | 529.51 NRS units*hours | Standard Deviation 147.247 |
| CA-008 15 mg (0.15 mg/mL) Cohort 3 | CA-008 Dose vs. Placebo Comparison: Area Under the Curve (AUC) 0 to 96 Hours | 532.14 NRS units*hours | Standard Deviation 188.144 |
| Placebo - Cohorts 2 and 3 | CA-008 Dose vs. Placebo Comparison: Area Under the Curve (AUC) 0 to 96 Hours | 539.43 NRS units*hours | Standard Deviation 217.047 |
p-value: 0.136Wilcoxon (Mann-Whitney)
p-value: 0.649Wilcoxon (Mann-Whitney)
p-value: 0.608Wilcoxon (Mann-Whitney)
Primary
Time-specific Mean Pain Intensity Scores (NRS) at Time 96 Hours for CA-008 vs. Placebo
Primary Efficacy Endpoint for the Pilot Stage. Time-specific mean pain intensity scores at Time 96 hours for CA-008 vs. placebo based on a 10-point numerical rating scale (NRS) from 0-10 where 0 is no pain and 10 is the worst pain imaginable).
Time frame: At 96 hours
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 | Time-specific Mean Pain Intensity Scores (NRS) at Time 96 Hours for CA-008 vs. Placebo | 3.8 scores on a scale | Standard Deviation 2.11 |
| Placebo - Cohort 1 | Time-specific Mean Pain Intensity Scores (NRS) at Time 96 Hours for CA-008 vs. Placebo | 5.1 scores on a scale | Standard Deviation 2.85 |
| CA-008 10 mg (0.1 mg/mL) Cohort 2 | Time-specific Mean Pain Intensity Scores (NRS) at Time 96 Hours for CA-008 vs. Placebo | 4.9 scores on a scale | Standard Deviation 2.02 |
| CA-008 15 mg (0.15 mg/mL) Cohort 3 | Time-specific Mean Pain Intensity Scores (NRS) at Time 96 Hours for CA-008 vs. Placebo | 4.8 scores on a scale | Standard Deviation 3.47 |
| Placebo - Cohorts 2 and 3 | Time-specific Mean Pain Intensity Scores (NRS) at Time 96 Hours for CA-008 vs. Placebo | 5.5 scores on a scale | Standard Deviation 2.91 |
p-value: 0.276ANOVA
p-value: 0.651ANOVA
p-value: 0.556ANOVA
Secondary
Percentage of Subjects Who do Not Require Opioids
Key Secondary Efficacy Endpoints for Stage 2. For each CA-008 dose vs. placebo comparison, percentage of subjects who do not require opioids.
Time frame: Time 0 hours to Time 96 hours: Opioid Free 0 hours to 96 hours
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 | Percentage of Subjects Who do Not Require Opioids | 0 Participants |
| Placebo - Cohort 1 | Percentage of Subjects Who do Not Require Opioids | 0 Participants |
| CA-008 10 mg (0.1 mg/mL) Cohort 2 | Percentage of Subjects Who do Not Require Opioids | 0 Participants |
| CA-008 15 mg (0.15 mg/mL) Cohort 3 | Percentage of Subjects Who do Not Require Opioids | 0 Participants |
| Placebo - Cohorts 2 and 3 | Percentage of Subjects Who do Not Require Opioids | 0 Participants |
Comparison: Not estimablep-value: 0Regression, Logistic
Comparison: Not estimablep-value: 0Regression, Logistic
Comparison: Not estimablep-value: 0Regression, Logistic
Secondary
Total Opioid Consumption (in Daily Oral Morphine Equivalents)
Key Secondary Efficacy Endpoints for Stage 2. Mean total postoperative opioid consumption (in daily oral morphine equivalents) for CA-008 compared to placebo
Time frame: OC from Time 0 hours to Time 96 hours: OC 0 hours to 96 hours
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CA-008 5 mg (0.05 mg/mL) Cohort 1 | Total Opioid Consumption (in Daily Oral Morphine Equivalents) | 244.17 mg morphine equivalents | Standard Deviation 170.578 |
| Placebo - Cohort 1 | Total Opioid Consumption (in Daily Oral Morphine Equivalents) | 321.33 mg morphine equivalents | Standard Deviation 137.462 |
| CA-008 10 mg (0.1 mg/mL) Cohort 2 | Total Opioid Consumption (in Daily Oral Morphine Equivalents) | 242.77 mg morphine equivalents | Standard Deviation 133.667 |
| CA-008 15 mg (0.15 mg/mL) Cohort 3 | Total Opioid Consumption (in Daily Oral Morphine Equivalents) | 365.25 mg morphine equivalents | Standard Deviation 201.161 |
| Placebo - Cohorts 2 and 3 | Total Opioid Consumption (in Daily Oral Morphine Equivalents) | 280.36 mg morphine equivalents | Standard Deviation 174.278 |
p-value: 0.306ANOVA
p-value: 0.595ANOVA
p-value: 0.242ANOVA