Clinical trial NCT01361568: Study to Evaluate Analgesic Effect of IV Administration of Kappa Agonist CR845 For Hysterectomy Surgery
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Postoperative Pain
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
Lead sponsor: Cara Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2011-05-27
Enrollment: 203
Sex: FEMALE
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Total Morphine Consumption in the First 24 Hours Following Postoperative Study Drug Treatment
timeFrame: 24 hours
Secondary outcomes:
measure: Summed Pain Intensity Difference From 0-24 Hours (SPID 0-24) Following Postoperative Study Drug Treatment Using Last Observation Carried Forward (LOCF)
timeFrame: 0 to 24 hours
measure: Morphine Consumption Following Postoperative Study Drug Treatment in the 2-24 Hour Period After Recovery in the Post-Anesthesia Care Unit (Post-PACU)
timeFrame: 2 to 24 hours (post-PACU)
measure: Total Pain Relief Within the First 2 Hours (TOTPAR 0-2) Following Postoperative Study Drug Treatment Using LOCF
timeFrame: 0 to 2 hours
measure: Global Evaluation Responder Analysis
timeFrame: At 24 hours
measure: Total Number of Patients Reporting At Least One Episode of Nausea
timeFrame: Up to 24 hours
measure: Total Number of Patients Reporting At Least One Episode of Vomiting
timeFrame: Up to 24 hours
Other outcomes:
Locations:
city: Florence
country: United States
facility: Shoals Clinical Research Associates
state: Alabama
city: Mobile
country: United States
facility: Horizon Research Group
state: Alabama
city: Mobile
country: United States
facility: Wilmax
state: Alabama
city: Montgomery
country: United States
facility: Drug Research and Analysis Corp
state: Alabama
city: Sheffield
country: United States
facility: Shoals Medical Trials, INC
state: Alabama
city: Phoenix
country: United States
facility: Precision Clinical Trials
state: Arizona
city: Davis
country: United States
facility: Woodland Healthcare California Clinical Research, Inc
state: California
city: Sylmar
country: United States
facility: Olive View-UCLA Medical Center
state: California
city: Boynton Beach
country: United States
facility: Visions Clinical Research
state: Florida
city: Edgewater
country: United States
facility: Riverside Clinical Research
state: Florida
city: Miami
country: United States
facility: University of Miami, Dept of
state: Florida
city: Wichita
country: United States
facility: Cypress Medical Research
state: Kansas
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Medical, Dept of Anesthesia
state: Ohio
city: Greenville
country: United States
facility: Palmetto Clinical Research,
state: South Carolina
city: Chattanooga
country: United States
facility: Chattanooga Medical Research
state: Tennessee
city: Fort Worth
country: United States
facility: Texas Health Care, PLLC
state: Texas
Study officials:
affiliation: Duke University
name: Tong-Joo Gan, MD, MHS
role: PRINCIPAL_INVESTIGATOR
References: