Acute Pain
Conditions
Keywords
pain, acute pain, kappa agonis, opioid analgesia, bunionectomy, peripheral nervous system agents, physiological effects of drugs, surgery, post-operative, post-operative complications
Brief summary
This is a single-center, randomized, double blind, placebo controlled, parallel group proof of concept study to evaluate the analgesic efficacy as well as the safety, tolerability and pharmacokinetic profile of CR845 in patients with pain following bunionectomy surgery.
Detailed description
Currently, the most widely used drugs to treat pain after surgery are opiates, such as morphine. Morphine works mainly by activating one of several types of opiate receptors that control some of our pain sensation - the so-called mu opiate receptors. These receptors are located in many areas of the brain and also outside of the brain. By activating these receptors, morphine provides significant pain relief, but also causes side effects that limit its use. Some of these side effects include: respiratory depression or arrest (slowed or stopped breathing), sedation (a state of calmness or extreme relaxation), euphoria (an exaggerated feeling of physical and mental well-being), constipation, nausea, vomiting, and drug addiction. In order to avoid the side effects of morphine and other mu opiates, the present experimental drug CR845 was designed to work at a different type of opiate receptor - called kappa - that can also provide pain relief, by acting on sensory nerves outside the brain. CR845 was designed to penetrate the brain much less than other opiate drugs, which should result in pain relief similar to that of morphine, but with fewer side effects. Because CR845 activates kappa receptors instead of mu receptors, the side effects are different than with a morphine-type drug. In particular, kappa opiates, such as CR845, do not cause respiratory depression or arrest, euphoria, constipation, drug tolerance, physical drug dependence or drug addiction. For these reasons, CR845 may present a distinct advantage over other opiates that are currently used for pain relief and post-operative pain in particular.
Interventions
DRUGCR845
CR845 dosage = 0.005 mg/kg per dose, IV bolus. The initial dose was administered upon reaching a qualifying pain intensity score and followed by a supplemental dose, if requested by patient for pain. Additional doses could be administered every 8 hours up to 48 hours.
DRUGPlacebo
Matching placebo administered using same dosing algorithm as the active arm
Sponsors
Cara Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able to provide written informed consent prior to any study procedures; 2. Able to communicate clearly with the Investigator and staff; 3. Males and females aged 18 years or older; 4. Scheduled for elective primary unilateral first metatarsal bunionectomy surgery (osteotomy and internal fixation) with no collateral procedures; 5. Females physically incapable of childbearing potential (postmenopausal for more than 1 year or surgically sterile) or practicing an acceptable method of contraception (hormonal, barrier with spermicide, intrauterine device, vasectomized partner, or abstinence). Subjects using hormonal birth control must have received at least 1 cycle of treatment prior to randomization. All females of childbearing potential must have a negative pregnancy test and not be breast feeding at Baseline; 6. Negative urine drug screen for drugs of abuse at Screening and at Baseline; a positive drug screen result may be permitted if the patient has been on a stable dose of an allowed medication for \>30 days (antipsychotics, antiepileptics, sedatives, hypnotics, or antianxiety agents, selective serotonin reuptake inhibitors \[SSRIs\], tricyclic antidepressants) or \>3 months (opioid analgesics or systemic steroids); 7. American Society of Anesthesiologists (ASA) risk class of I to II; 8. Body weight \<170 kg
Exclusion criteria
1. Has known allergies to opioids, unless has subsequently tolerated other opioids and in the opinion of the PI could tolerate study drug; 2. Has a known or suspected history of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-diagnosed alcohol, opiate or other drug abuse or dependence within 12 months prior to screening; 3. Is unable to refrain from alcohol consumption for a period beginning 24 hours prior to surgery through the end of the Treatment Period; 4. Has taken non-opioid analgesics (including cyclooxygenase-2 \[COX-2\] inhibitors) or nonsteroidal anti-inflammatory drugs (NSAIDs) within 12 hours of the Baseline assessments; 5. Has taken any opioid analgesics or used systemic steroids within 4 days of surgery OR has been using opiates chronically for a period of \< 3 months; (Note: Patients on stable chronic opioids for ≥ 3 months will need to discontinue them for 4 days prior to surgery); 6. Has used antipsychotics, antiepileptics, sedatives, hypnotics, or antianxiety agents, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants for \< 30 days prior to surgery or had a dose change within the previous 30 days; 7. Has taken any prescription or over-the-counter medication within 4 days prior to surgery that, in the opinion of the Investigator, is expected to confound the analgesic response; 8. Has taken herbal agents or nutraceuticals (i.e., chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, skullcap, St. John's wort, or valerian) during any of the 7 days prior to surgery; 9. Has any clinically significant condition or a significant laboratory abnormality that would, in the Investigator's or designee's opinion, preclude study participation 10. Has received another investigational drug within 30 days of scheduled surgery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summed Pain Intensity Differences Over 24 Hours (SPID 0-24) Following the Initial Administration of Study Drug | 0 to 24 hours | Patients reported their pain intensity using a visual analogue scale (VAS) from 0 to 100 mm, where 0 mm represented No Pain and 100 mm represented the Worst Pain You Can Imagine. SPID 0-24 represents the cumulative time-weighted sum of the pain intensity difference (PID) scores between each assessment timepoint following the postoperative administration of study drug (i.e. 0 to 15 min, 15 to 30 min, etc.) over 24 hours. Pain intensity assessments were measured at baseline (entry pain score) and at 15, 30, 45, 60, 90, 120 and 150 minutes; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 hours after the first administration of study drug (only timepoints up to 24 hours used in calculating SPID 0-24). Negative SPID values represent a decrease in pain intensity (i.e. lower values indicate a greater reduction in pain). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summed Pain Intensity Differences Over 36 Hours (SPID 0-36) Following the Initial Administration of Study Drug | Up to 36 hours | Patients reported their pain intensity using a visual analogue scale (VAS) from 0 to 100 mm, where 0 mm represented No Pain and 100 mm represented the Worst Pain You Can Imagine. SPID 0-24 represents the cumulative time-weighted sum of the pain intensity difference (PID) scores between each assessment timepoint following the postoperative administration of study drug (i.e. 0 to 15 min, 15 to 30 min, etc.) over 24 hours. Pain intensity assessments were measured at baseline (entry pain score) and at 15, 30, 45, 60, 90, 120 and 150 minutes; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 hours after the first administration of study drug (only timepoints up to 36 hours used in calculating SPID 0-36). Negative SPID values represent a decrease in pain intensity (i.e. lower values indicate a greater reduction in pain). |
| Summed Pain Intensity Differences Over 48 Hours (SPID 0-48) Following the Initial Administration of Study Drug | Up to 48 hours | Patients reported their pain intensity using a visual analogue scale (VAS) from 0 to 100 mm, where 0 mm represented No Pain and 100 mm represented the Worst Pain You Can Imagine. SPID 0-24 represents the cumulative time-weighted sum of the pain intensity difference (PID) scores between each assessment timepoint following the postoperative administration of study drug (i.e. 0 to 15 min, 15 to 30 min, etc.) over 24 hours. Pain intensity assessments were measured at baseline (entry pain score) and at 15, 30, 45, 60, 90, 120 and 150 minutes; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 hours after the first administration of study drug. Negative SPID values represent a decrease in pain intensity (i.e. lower values indicate a greater reduction in pain). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CR845 CR845 (0.005 mg/kg) IV | 34 |
| Placebo Matched placebo | 17 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lack of Efficacy | 6 | 2 |
| Overall Study | Unable to get IV access | 1 | 0 |
Baseline characteristics
| Characteristic | CR845 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 16 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 17 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 15 Participants | 47 Participants |
| Region of Enrollment United States | 34 participants | 17 participants | 51 participants |
| Sex: Female, Male Female | 29 Participants | 16 Participants | 45 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 29 / 34 | 14 / 17 |
| serious Total, serious adverse events | 0 / 34 | 0 / 17 |
Outcome results
Primary
Summed Pain Intensity Differences Over 24 Hours (SPID 0-24) Following the Initial Administration of Study Drug
Patients reported their pain intensity using a visual analogue scale (VAS) from 0 to 100 mm, where 0 mm represented No Pain and 100 mm represented the Worst Pain You Can Imagine. SPID 0-24 represents the cumulative time-weighted sum of the pain intensity difference (PID) scores between each assessment timepoint following the postoperative administration of study drug (i.e. 0 to 15 min, 15 to 30 min, etc.) over 24 hours. Pain intensity assessments were measured at baseline (entry pain score) and at 15, 30, 45, 60, 90, 120 and 150 minutes; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 hours after the first administration of study drug (only timepoints up to 24 hours used in calculating SPID 0-24). Negative SPID values represent a decrease in pain intensity (i.e. lower values indicate a greater reduction in pain).
Time frame: 0 to 24 hours
Population: The analysis included all patients in the Completer population who completed the trial, where time 0 was the start time of the first dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Summed Pain Intensity Differences Over 24 Hours (SPID 0-24) Following the Initial Administration of Study Drug | -52.08 units on a scale * hours | Standard Deviation 395.02 |
| CR845 | Summed Pain Intensity Differences Over 24 Hours (SPID 0-24) Following the Initial Administration of Study Drug | -292.7 units on a scale * hours | Standard Deviation 390.52 |
p-value: <0.05ANOVA
Secondary
Summed Pain Intensity Differences Over 36 Hours (SPID 0-36) Following the Initial Administration of Study Drug
Patients reported their pain intensity using a visual analogue scale (VAS) from 0 to 100 mm, where 0 mm represented No Pain and 100 mm represented the Worst Pain You Can Imagine. SPID 0-24 represents the cumulative time-weighted sum of the pain intensity difference (PID) scores between each assessment timepoint following the postoperative administration of study drug (i.e. 0 to 15 min, 15 to 30 min, etc.) over 24 hours. Pain intensity assessments were measured at baseline (entry pain score) and at 15, 30, 45, 60, 90, 120 and 150 minutes; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 hours after the first administration of study drug (only timepoints up to 36 hours used in calculating SPID 0-36). Negative SPID values represent a decrease in pain intensity (i.e. lower values indicate a greater reduction in pain).
Time frame: Up to 36 hours
Population: The analysis included all patients in the Completer population who completed the trial, where time 0 was the start time of the first dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Summed Pain Intensity Differences Over 36 Hours (SPID 0-36) Following the Initial Administration of Study Drug | -259.2 units on a scale * hours | Standard Deviation 533.24 |
| CR845 | Summed Pain Intensity Differences Over 36 Hours (SPID 0-36) Following the Initial Administration of Study Drug | -675.6 units on a scale * hours | Standard Deviation 658 |
p-value: <0.03ANOVA
Secondary
Summed Pain Intensity Differences Over 48 Hours (SPID 0-48) Following the Initial Administration of Study Drug
Patients reported their pain intensity using a visual analogue scale (VAS) from 0 to 100 mm, where 0 mm represented No Pain and 100 mm represented the Worst Pain You Can Imagine. SPID 0-24 represents the cumulative time-weighted sum of the pain intensity difference (PID) scores between each assessment timepoint following the postoperative administration of study drug (i.e. 0 to 15 min, 15 to 30 min, etc.) over 24 hours. Pain intensity assessments were measured at baseline (entry pain score) and at 15, 30, 45, 60, 90, 120 and 150 minutes; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 hours after the first administration of study drug. Negative SPID values represent a decrease in pain intensity (i.e. lower values indicate a greater reduction in pain).
Time frame: Up to 48 hours
Population: The analysis included all patients in the Completer population who completed the trial, where time 0 was the start time of the first dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Summed Pain Intensity Differences Over 48 Hours (SPID 0-48) Following the Initial Administration of Study Drug | -534.4 units on a scale * hours | Standard Deviation 724.8 |
| CR845 | Summed Pain Intensity Differences Over 48 Hours (SPID 0-48) Following the Initial Administration of Study Drug | -1117 units on a scale * hours | Standard Deviation 954.8 |
p-value: <0.03ANOVA