Study to Evaluate Analgesic Effect of Intravenous Administration of Kappa Agonist CR845 After Hysterectomy Surgery

Study Overview
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Brief Summary
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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
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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 Phase 2, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept Study to Evaluate the Analgesic Efficacy and Safety of Intravenous CR845 During the Post-Operative Period in Subjects Undergoing Laparoscopic-Assisted Hysterectomy

Conditions
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Acute Pain

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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 60 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CR845<br>CR845 administered as a single 15-min i.v. infusion at doses of 0.008 or 0.024 mg/kg on the day after surgery (Cohort 1), or at a dose of 0.040 mg/kg immediately after surgery (Cohort 2) | Drug: CR845<br>* CR845 (0.024 mg/kg) administered the day after surgery (Day 1)<br>* Other names: Cohort 1: CR845 0.024 mg/kg;Drug: CR845<br>* CR845 (0.008 mg/kg) administered the day after surgery (Day 1)<br>* Other names: Cohort 1: CR845 0.008 mg/kg;Drug: CR845<br>* CR845 (0.040 mg/kg) administered immediately after surgery (Day 0)<br>* Other names: Cohort 2: CR845 0.040 mg/kg;|
| Placebo Comparator: Placebo<br>Matched placebo administered as a single 15-min i.v. infusion on the day after surgery (Cohort 1), or the immediately after surgery (Cohort 2) | Drug: Placebo<br>* Matched placebo administered the day after surgery (Day 1)<br>* Other names: Cohort 1: Matched placebo;Drug: Placebo<br>* Matched placebo administered immediately after surgery (Day 0)<br>* Other names: Cohort 2: Matched placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 15 and 30 minutes after study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total PCA Morphine Consumption in the 0-16 Hour Period Following Postoperative Study Drug Treatment |  | 0 to 16 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