Study to Evaluate Analgesic Effect of IV Administration of Kappa Agonist CR845 For Hysterectomy Surgery

Study Overview
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Brief Summary
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The primary purpose of this study is to determine if CR845 is effective in treating the pain associated with a laparoscopic hysterectomy.

Detailed Description
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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.

Official Title
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A Multi-Center, Double-Randomized, Double Blind, Placebo Controlled Study to Evaluate the Analgesic Efficacy and Safety of Intravenous CR845 Dosed Preoperatively and Postoperatively in Patients Undergoing a Laparoscopic Hysterectomy

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: CR845
* Drug: Placebo
* Drug: CR845
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CR845<br>Peripheral kappa opioid receptor agonist | Drug: CR845<br>* Single i.v. dose (0.04 mg/kg) administered preoperatively<br>* Other names: Preoperative Active Dose;Drug: CR845<br>* Single i.v. dose (0.04 mg/kg) administered postoperatively for pain<br>* Other names: Postoperative Active for Pain;|
| Placebo Comparator: Placebo<br>Matched Placebo | Drug: Placebo<br>* Single i.v. dose administered preoperatively<br>* Other names: Preoperative Placebo Dose;Drug: Placebo<br>* Single i.v. dose administered postoperatively for pain<br>* Other names: Postoperative Placebo for Pain;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Morphine Consumption in the First 24 Hours Following Postoperative Study Drug Treatment |  | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 0 to 24 hours | 
| 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 | 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. | 0 to 2 hours | 
| 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. | At 24 hours | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, acute pain, visceral pain, kappa agonist, opioid analgesics, peripheral nervous system agents, physiological effects of drugs, surgery, hysterectomy, post-operative, post-operative complications