Acute Pain
Conditions
Keywords
pain, acute pain, visceral pain, kappa agonist, opioid analgesics, peripheral nervous system agents, physiological effects of drugs, surgery, hysterectomy, post-operative, post-operative complications
Brief summary
The purpose of this study is to determine the effectiveness and safety of single intravenous doses of the kappa opioid agonist CR845 in relieving pain in patients following laparoscopic-assisted hysterectomy surgery. The study protocol was divided into two parts with subjects either dosed with study drug the day following surgery (Cohort 1), or immediately after surgery (Cohort 2).
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 (0.024 mg/kg) administered the day after surgery (Day 1)
DRUGPlacebo
Matched placebo administered the day after surgery (Day 1)
Sponsors
Cara Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* The patients will have an elective laparoscopic-assisted hysterectomy under general anesthesia. * The patient's preoperative health is graded as the American Society of Anesthesiologists (ASA) risk class of I to III
Exclusion criteria
* The patient has a history of known allergies to opioids * The patient is currently taking opioid analgesics chronically or took opioid analgesics on at least 4 days during the week before surgery. * Patients having additional procedures (such as those involving the bladder) at the same time as the laparoscopic-assisted hysterectomy. * Patients taking short-acting oral analgesics (eg, acetaminophen, aspirin, ibuprofen, ketorolac) within 6 hours before administration of study drug; long-acting nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, naproxen, oxaprozin, piroxicam, celecoxib) within 3 days before administration of study drug; systemic steroids within 72 hours before administration of study drug; or any opioid analgesics or tramadol daily for greater than 10 days of the last 30 days before administration of study drug. * Patients taking the following herbal agents or nutraceuticals within 7 days prior to beginning of the study: chaparral, comfrey, germander, gin bu huan, kava, pennyroyal, skullcap, St. John's wort, or valerian. * Patients with clinically significant cardiovascular disease, or cardiac arrhythmias, or significant major risk factors for cardiovascular disease such as poorly controlled hypertension, poorly controlled hypercholesterolemia, poorly controlled diabetes mellitus or serious medical conditions, such as cancer. * Patient has a history of hepatitis B or C or HIV infection with positive hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus (HCV) antibody test.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Responders on Pain Intensity(PI) and Pain Relief (PR) Composite Endpoint | 15 and 30 minutes after study drug administration | The primary efficacy endpoint was the percentage of treatment responders compared to placebo. A responder was defined as a subject who had at least a 40% reduction in their pain intensity score and a pain relief score of some, a lot, or complete at 15 and 30 min following the start of the study drug infusion. |
Secondary
| Measure | Time frame |
|---|---|
| Total PCA Morphine Consumption in the 0-16 Hour Period Following Postoperative Study Drug Treatment | 0 to 16 hours |
Other
| Measure | Time frame |
|---|---|
| Total PCA Morphine Consumption in the 4-8 Hour Period Following Postoperative Study Drug Treatment | 4 to 8 hours |
| Total PCA Morphine Consumption in the 8-16 Hour Period Following Postoperative Study Drug Treatment | 8 to 16 hours |
Countries
United States
Participant flow
Recruitment details
Two cohorts of patients were enrolled in this study in sequential order. Based on interim analysis of the results for Cohort 1 where study drug was administered 24 hours following surgery, the protocol was revised to administer the study drug immediately following surgery when patients were more likely to report a higher level of pain.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Placebo Matched placebo administered 24 hours post-surgery (Day 1) | 25 |
| Cohort 1: CR845 0.008 mg/kg CR845 (0.008 mg/kg) single i.v. dose administered 24 hours post-surgery (Day 1) | 22 |
| Cohort 1: CR845 0.024 mg/kg CR845 (0.024 mg/kg) single i.v. dose administered 24 hours post-surgery (Day 1) | 21 |
| Cohort 2: Placebo Matched placebo administered within 3 hours post-surgery (Day 0) | 26 |
| Cohort 2: CR845 0.040 mg/kg CR845 (0.040 mg/kg) single i.v. dose administered within 3 hours post-surgery (Day 0) | 20 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Cohort 1: 24 Hours After Surgery (Day 1) | Adverse Event | 2 | 1 | 1 | 0 | 0 |
| Cohort 1: 24 Hours After Surgery (Day 1) | Lost to Follow-up | 1 | 1 | 2 | 0 | 0 |
| Cohort 1: 24 Hours After Surgery (Day 1) | Withdrawal by Subject | 0 | 3 | 0 | 0 | 0 |
| Cohort 2: Immediately Post-op (Day 0) | Lost to Follow-up | 0 | 0 | 0 | 1 | 1 |
| Cohort 2: Immediately Post-op (Day 0) | Protocol Violation | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: CR845 0.024 mg/kg | Cohort 1: Placebo | Cohort 1: CR845 0.008 mg/kg | Cohort 2: Placebo | Cohort 2: CR845 0.040 mg/kg | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 25 Participants | 22 Participants | 26 Participants | 20 Participants | 114 Participants |
| Region of Enrollment United States | 21 participants | 25 participants | 22 participants | 26 participants | 20 participants | 114 participants |
| Sex: Female, Male Female | 21 Participants | 25 Participants | 22 Participants | 26 Participants | 20 Participants | 114 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 | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 25 | 14 / 22 | 18 / 21 | 14 / 26 | 12 / 20 |
| serious Total, serious adverse events | 2 / 25 | 1 / 22 | 2 / 21 | 1 / 26 | 3 / 20 |
Outcome results
Primary
Responders on Pain Intensity(PI) and Pain Relief (PR) Composite Endpoint
The primary efficacy endpoint was the percentage of treatment responders compared to placebo. A responder was defined as a subject who had at least a 40% reduction in their pain intensity score and a pain relief score of some, a lot, or complete at 15 and 30 min following the start of the study drug infusion.
Time frame: 15 and 30 minutes after study drug administration
Population: Results are for Cohort 2 (study drug administered within 3 hours after surgery), ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2: Placebo | Responders on Pain Intensity(PI) and Pain Relief (PR) Composite Endpoint | 1 responders |
| Cohort 2: CR845 0.040 mg/kg | Responders on Pain Intensity(PI) and Pain Relief (PR) Composite Endpoint | 1 responders |
Secondary
Total PCA Morphine Consumption in the 0-16 Hour Period Following Postoperative Study Drug Treatment
Time frame: 0 to 16 hours
Population: Results are for Cohort 2 (study drug administered within 3 hours after surgery), ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Placebo | Total PCA Morphine Consumption in the 0-16 Hour Period Following Postoperative Study Drug Treatment | 24.0 mg | Standard Deviation 15.4 |
| Cohort 2: CR845 0.040 mg/kg | Total PCA Morphine Consumption in the 0-16 Hour Period Following Postoperative Study Drug Treatment | 15.8 mg | Standard Deviation 11.8 |
p-value: 0.057t-test, 2 sided
Other Pre-specified
Total PCA Morphine Consumption in the 4-8 Hour Period Following Postoperative Study Drug Treatment
Time frame: 4 to 8 hours
Population: Results are for Cohort 2 (study drug administered within 3 hours after surgery), ITT population, based on the number of evaluable patients over the 4-8 hour time interval.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Placebo | Total PCA Morphine Consumption in the 4-8 Hour Period Following Postoperative Study Drug Treatment | 5.9 mg | Standard Deviation 4.56 |
| Cohort 2: CR845 0.040 mg/kg | Total PCA Morphine Consumption in the 4-8 Hour Period Following Postoperative Study Drug Treatment | 2.9 mg | Standard Deviation 2.63 |
p-value: <0.05t-test, 2 sided
Other Pre-specified
Total PCA Morphine Consumption in the 8-16 Hour Period Following Postoperative Study Drug Treatment
Time frame: 8 to 16 hours
Population: Results are for Cohort 2 (study drug administered within 3 hours after surgery), ITT population, based on the number of evaluable patients over the 8-16 hour time interval.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Placebo | Total PCA Morphine Consumption in the 8-16 Hour Period Following Postoperative Study Drug Treatment | 6.5 mg | Standard Deviation 5.28 |
| Cohort 2: CR845 0.040 mg/kg | Total PCA Morphine Consumption in the 8-16 Hour Period Following Postoperative Study Drug Treatment | 13.8 mg | Standard Deviation 11.5 |
p-value: <0.01t-test, 2 sided