Postoperative 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 primary purpose of this study is to determine if CR845 is effective in treating the pain associated with a laparoscopic hysterectomy.
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
Single i.v. dose (0.04 mg/kg) administered preoperatively
DRUGPlacebo
Single i.v. dose administered preoperatively
Sponsors
Cara Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Able to provide written informed consent prior to any study procedures; * Able to communicate clearly with the Investigator and staff; * Female between 21 and 65 years of age, inclusive; * Scheduled for elective laparoscopic hysterectomy under general anesthesia; * Negative result on serum pregnancy test at screening and negative urine pregnancy test at Baseline (for women of child-bearing potential only) and not currently breast feeding, or planning to do so within 30 days of dosing; * Negative urine drug screen for drugs of abuse at Screening and at Baseline; * American Society of Anesthesiologists (ASA) risk class of I to III; * Body mass index (BMI) between 17 and 40 inclusive.
Exclusion criteria
* Has known allergies to opioids, or hypersensitivity to other materials (such as infusion line) or medications to be used in the study; * 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; * Is unable to refrain from alcohol consumption for a period beginning 24 hours prior to surgery through the end of the Treatment Period; * Is scheduled to undergo a hysterectomy that will utilize any type of robotic technology and/or a concomitant surgical procedure that would produce a significantly greater degree of surgical trauma than the laparoscopic hysterectomy or laparoscopic assisted vaginal hysterectomy alone; * Has taken non-opioid analgesics (including cyclooxygenase-2 \[COX-2\] inhibitors) or nonsteroidal anti-inflammatory drugs (NSAIDs) within 12 hours of the Baseline assessments; * Has taken any opioid analgesics or used systemic steroids within 4 days of surgery OR has previously used opiates chronically for a period of ≥3 months; * 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; * Has taken any prescription or over-the-counter medication within 3 days prior to surgery that, in the opinion of the Investigator, is expected to confound the analgesic response; * Has taken herbal agents or nutraceuticals (i.e., chaparral, comfrey, germander, gin bu huan, kava, pennyroyal, skullcap, St. John's wort, or valerian) 7 days prior to surgery; * In the opinion of Investigator shows clinical signs of hypovolemia; * Has an oxygen saturation \< 92% on room air at Screening or prior to receiving the first infusion of study drug; * Has any history of clinically significant cardiovascular disease, * Has a clinically significant abnormal electrocardiogram (ECG) or a history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome); * Has a history of any serious medical conditions that in the opinion of the Investigator would preclude study participation; * Has serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, or gamma glutamyl transferase (GGT) \>2.5 x the upper limit of normal (ULN) at screening; * Has bilirubin, blood urea nitrogen (BUN), or creatinine \>1.5 x the reference ULN at Screening; * Has abnormally low hemoglobin \< 10 mg/dl at Screening; * Has serum sodium levels \> 146 mmol/L at Screening; * Has impaired renal function (creatinine clearance \[CrCl\] \< 50 ml/min) at Screening; * Has a positive test for human immunodeficiency virus (HIV) or known history of HIV infection; * Has received another investigational drug within 30 days of scheduled surgery; * Has a significant chronic pain condition in areas unrelated to the operative site at the time of Screening that in the Investigator's opinion could confound the interpretation of study results
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Total Morphine Consumption in the First 24 Hours Following Postoperative Study Drug Treatment | 24 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Morphine Consumption Following Postoperative Study Drug Treatment in the 2-24 Hour Period After Recovery in the Post-Anesthesia Care Unit (Post-PACU) | 2 to 24 hours (post-PACU) | — |
| Total Pain Relief Within the First 2 Hours (TOTPAR 0-2) Following Postoperative Study Drug Treatment Using LOCF | 0 to 2 hours | Patients reported their pain relief using a 5-point categorical scale of 0 to 4 (0 = No Relief, 1 = A Little Relief, 2 = Some Relief, 3 = A Lot of Relief and 4 = Complete Relief). TOTPAR 0-2 was represents the cumulative time-weighted sum of the pain relief (PR) scores between each assessment timepoint following the postoperative administration of study drug (i.e. 15 to 30 min, 30 to 45 min, etc.) over the first 2 hours. Pain relief assessments were measured at 15, 30, 45, 60, 90, 120 minutes after the start of the infusion of study drug following surgery. Positive TOTPAR values represent an increase in pain relief. |
| Summed Pain Intensity Difference From 0-24 Hours (SPID 0-24) Following Postoperative Study Drug Treatment Using Last Observation Carried Forward (LOCF) | 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), then at 15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, 720, 960, and 1440 minutes after the start of the infusion of study drug following surgery. Negative SPID values represent a decrease in pain intensity (i.e. lower values indicate a greater reduction in pain). |
| Total Number of Patients Reporting At Least One Episode of Nausea | Up to 24 hours | — |
| Total Number of Patients Reporting At Least One Episode of Vomiting | Up to 24 hours | — |
| Global Evaluation Responder Analysis | At 24 hours | Responders = Excellent or Very Good; Non-Responders = Fair or Poor. Patient who reported a score of Good were not included in the analysis as the midpoint cannot be unambiguously assigned for a binary outcome measurement. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo-Placebo Placebo administered both preoperatively and postoperatively | 71 |
| Placebo-CR845 Placebo administered preoperatively and CR845 administered postoperatively | 71 |
| CR845-CR845 CR845 administered both preoperatively and postoperatively | 20 |
| CR845-Placebo CR845 administered preoperatively and placebo administered postoperatively | 21 |
| CR845-No Postoperative Treatment CR845 administered preoperatively and no study drug administered postoperatively | 7 |
| Placebo-No Postoperative Treatment Placebo administered preoperatively and no study drug administered postoperatively | 13 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo-CR845 | CR845-CR845 | CR845-Placebo | Placebo-Placebo | CR845-No Postoperative Treatment | Placebo-No Postoperative Treatment | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 70 Participants | 20 Participants | 21 Participants | 71 Participants | 7 Participants | 13 Participants | 202 Participants |
| Age, Continuous | 44.3 years STANDARD_DEVIATION 9.69 | 43.8 years STANDARD_DEVIATION 7.14 | 40.0 years STANDARD_DEVIATION 6.88 | 42.7 years STANDARD_DEVIATION 8.6 | 55.9 years STANDARD_DEVIATION 7.84 | 45.3 years STANDARD_DEVIATION 7.93 | 43.7 years STANDARD_DEVIATION 8.97 |
| Region of Enrollment United States | 71 participants | 20 participants | 21 participants | 71 participants | 7 participants | 13 participants | 203 participants |
| Sex: Female, Male Female | 71 Participants | 20 Participants | 21 Participants | 71 Participants | 7 Participants | 13 Participants | 203 Participants |
| Sex: Female, Male Male | 0 Participants | 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 59 / 71 | 62 / 71 | 19 / 20 | 15 / 21 | 7 / 7 | 10 / 13 |
| serious Total, serious adverse events | 0 / 71 | 6 / 71 | 3 / 20 | 0 / 21 | 3 / 7 | 1 / 13 |
Outcome results
Primary
Total Morphine Consumption in the First 24 Hours Following Postoperative Study Drug Treatment
Time frame: 24 hours
Population: The primary analysis included all patients in the modified Intent-to-Treat (mITT) population who re-randomized in the postoperative period, where time 0 was the start time of the postoperative study drug infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo-Placebo | Total Morphine Consumption in the First 24 Hours Following Postoperative Study Drug Treatment | 21.9 mg | Standard Error 1.89 |
| Placebo-CR845 | Total Morphine Consumption in the First 24 Hours Following Postoperative Study Drug Treatment | 17.6 mg | Standard Error 1.65 |
| CR845-CR845 | Total Morphine Consumption in the First 24 Hours Following Postoperative Study Drug Treatment | 13.9 mg | Standard Error 2.2 |
| CR845-Placebo | Total Morphine Consumption in the First 24 Hours Following Postoperative Study Drug Treatment | 19.8 mg | Standard Error 3.03 |
p-value: <0.0595% CI: [-15.14, -0.78]t-test, 2 sided
Secondary
Global Evaluation Responder Analysis
Responders = Excellent or Very Good; Non-Responders = Fair or Poor. Patient who reported a score of Good were not included in the analysis as the midpoint cannot be unambiguously assigned for a binary outcome measurement.
Time frame: At 24 hours
Population: The responder analysis included all patients in the modified Intent-to-Treat (mITT) population and compared patients that received any dose of CR845 (preoperatively and/or postoperatively) to patients that only received placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo-Placebo | Global Evaluation Responder Analysis | 27 Responder Count |
| Placebo-CR845 | Global Evaluation Responder Analysis | 68 Responder Count |
p-value: 0.001Chi-squared
Secondary
Morphine Consumption Following Postoperative Study Drug Treatment in the 2-24 Hour Period After Recovery in the Post-Anesthesia Care Unit (Post-PACU)
Time frame: 2 to 24 hours (post-PACU)
Population: The analysis included all patients in the modified Intent-to-Treat (mITT) population who re-randomized in the postoperative period, where time 0 was the start time of the postoperative study drug infusion. Morphine consumption was calculated for the 2-24 hour period, after patients were transferred out of the PACU.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo-Placebo | Morphine Consumption Following Postoperative Study Drug Treatment in the 2-24 Hour Period After Recovery in the Post-Anesthesia Care Unit (Post-PACU) | 14.38 mg | Standard Error 1.35 |
| Placebo-CR845 | Morphine Consumption Following Postoperative Study Drug Treatment in the 2-24 Hour Period After Recovery in the Post-Anesthesia Care Unit (Post-PACU) | 11.07 mg | Standard Error 1.17 |
| CR845-CR845 | Morphine Consumption Following Postoperative Study Drug Treatment in the 2-24 Hour Period After Recovery in the Post-Anesthesia Care Unit (Post-PACU) | 7.99 mg | Standard Error 2.03 |
| CR845-Placebo | Morphine Consumption Following Postoperative Study Drug Treatment in the 2-24 Hour Period After Recovery in the Post-Anesthesia Care Unit (Post-PACU) | 11.33 mg | Standard Error 2.11 |
p-value: <0.05Mixed Models Analysis
p-value: 0.059Mixed Models Analysis
Secondary
Summed Pain Intensity Difference From 0-24 Hours (SPID 0-24) Following Postoperative Study Drug Treatment Using Last Observation Carried Forward (LOCF)
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), then at 15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, 720, 960, and 1440 minutes after the start of the infusion of study drug following surgery. 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 modified Intent-to-Treat (mITT) population who re-randomized in the postoperative period, where time 0 was the start time of the postoperative study drug infusion, and did not have a missing baseline pain intensity score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo-Placebo | Summed Pain Intensity Difference From 0-24 Hours (SPID 0-24) Following Postoperative Study Drug Treatment Using Last Observation Carried Forward (LOCF) | -413.1 units on a scale * hours | Standard Error 67.8 |
| Placebo-CR845 | Summed Pain Intensity Difference From 0-24 Hours (SPID 0-24) Following Postoperative Study Drug Treatment Using Last Observation Carried Forward (LOCF) | -643.2 units on a scale * hours | Standard Error 58.11 |
| CR845-CR845 | Summed Pain Intensity Difference From 0-24 Hours (SPID 0-24) Following Postoperative Study Drug Treatment Using Last Observation Carried Forward (LOCF) | -833.1 units on a scale * hours | Standard Error 124.8 |
| CR845-Placebo | Summed Pain Intensity Difference From 0-24 Hours (SPID 0-24) Following Postoperative Study Drug Treatment Using Last Observation Carried Forward (LOCF) | -673.5 units on a scale * hours | Standard Error 152.36 |
p-value: <0.01t-test, 2 sided
p-value: <0.05t-test, 2 sided
p-value: 0.068t-test, 2 sided
Secondary
Total Number of Patients Reporting At Least One Episode of Nausea
Time frame: Up to 24 hours
Population: All patients in the modified Intent-to-Treat (mITT) population and compared patients that received any dose of CR845 (preoperatively and/or postoperatively) to patients that only received placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo-Placebo | Total Number of Patients Reporting At Least One Episode of Nausea | 51.2 percentage of patients |
| Placebo-CR845 | Total Number of Patients Reporting At Least One Episode of Nausea | 26.1 percentage of patients |
p-value: <0.001Fisher Exact
Secondary
Total Number of Patients Reporting At Least One Episode of Vomiting
Time frame: Up to 24 hours
Population: All patients in the modified Intent-to-Treat (mITT) population and compared patients that received any dose of CR845 (preoperatively and/or postoperatively) to patients that only received placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo-Placebo | Total Number of Patients Reporting At Least One Episode of Vomiting | 8.3 percentage of patients |
| Placebo-CR845 | Total Number of Patients Reporting At Least One Episode of Vomiting | 1.7 percentage of patients |
p-value: <0.05Fisher Exact
Secondary
Total Pain Relief Within the First 2 Hours (TOTPAR 0-2) Following Postoperative Study Drug Treatment Using LOCF
Patients reported their pain relief using a 5-point categorical scale of 0 to 4 (0 = No Relief, 1 = A Little Relief, 2 = Some Relief, 3 = A Lot of Relief and 4 = Complete Relief). TOTPAR 0-2 was represents the cumulative time-weighted sum of the pain relief (PR) scores between each assessment timepoint following the postoperative administration of study drug (i.e. 15 to 30 min, 30 to 45 min, etc.) over the first 2 hours. Pain relief assessments were measured at 15, 30, 45, 60, 90, 120 minutes after the start of the infusion of study drug following surgery. Positive TOTPAR values represent an increase in pain relief.
Time frame: 0 to 2 hours
Population: The analysis included all patients in the modified Intent-to-Treat (mITT) population who re-randomized in the postoperative period, where time 0 was the start time of the postoperative study drug infusion, and did not have a missing baseline pain intensity score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo-Placebo | Total Pain Relief Within the First 2 Hours (TOTPAR 0-2) Following Postoperative Study Drug Treatment Using LOCF | 1.4 units on a scale * hours | Standard Error 0.16 |
| Placebo-CR845 | Total Pain Relief Within the First 2 Hours (TOTPAR 0-2) Following Postoperative Study Drug Treatment Using LOCF | 2.1 units on a scale * hours | Standard Error 0.19 |
| CR845-CR845 | Total Pain Relief Within the First 2 Hours (TOTPAR 0-2) Following Postoperative Study Drug Treatment Using LOCF | 2.4 units on a scale * hours | Standard Error 0.48 |
| CR845-Placebo | Total Pain Relief Within the First 2 Hours (TOTPAR 0-2) Following Postoperative Study Drug Treatment Using LOCF | 1.5 units on a scale * hours | Standard Error 0.4 |
p-value: <0.0595% CI: [0.22, 1.82]t-test, 2 sided
p-value: <0.0595% CI: [0.11, 1.17]t-test, 2 sided