A Study to Evaluate the Efficacy and Safety of Tapentadol (CG5503) in the Treatment of Acute Pain After Abdominal Hysterectomy

Study Overview
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Brief Summary
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The main objective of this study is to demonstrate the efficacy and safety of multiple-dose application of three different oral doses of CG5503 IR (tapentadol immediate release) compared to placebo in women undergoing abdominal hysterectomy.

Detailed Description
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Subjects undergoing abdominal hysterectomy often experience moderate to severe acute pain post-surgery. Normally such pain is controlled when subjects receive repeated doses of opioid analgesics. However, opioid therapy is commonly associated with side effects such as nausea, vomiting, sedation, constipation, addiction, tolerance, and respiratory depression. Tapentadol (CG5503), a newly synthesized drug with an immediate release (IR) formulation, also acts as a centrally acting pain reliever but has a dual mode of action. The aim of this study is to investigate the effectiveness (level of pain control) and safety (side effects) of 3 dose levels of CG5503 IR compared with no drug (placebo) or one dose level of morphine (an opioid commonly used to treat post-surgical pain). This study is a randomized, double-blind (neither investigator nor patient will know which treatment was received), active- and placebo-controlled, parallel-group, multicenter study to evaluate the treatment of acute pain after abdominal hysterectomy. The study will include a blinded 72 hour in-patient phase immediately following hysterectomy, during which subjects will be treated with either 50-, 75-, or 100-mg CG5503 IR, a matched placebo, or 20-mg morphine, and pain relief will be periodically assessed. Assessments of pain relief include the pain intensity numeric rating scale (PI), pain relief numeric rating scale (PAR), and patient global impression of change scale (PGIC). Safety evaluations include monitoring of adverse events, physical examinations, and clinical laboratory tests. Venous blood samples will be collected for the determination of serum concentrations of CG5503 and morphine. The alternative study hypothesis is that at least 1 dose strength of CG5503 will be different from placebo in controlling pain at 24 hours (using the mean SPID at 24 hours).

Official Title
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A Randomized, Double-blind, Parallel-arm, Placebo- and Comparator- Controlled Trial of the Efficacy and Safety of Multiple Doses of Immediate-release (IR) CG5503 for Postoperative Pain Following Abdominal Hysterectomy

Conditions
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Hysterectomy, Postoperative

Intervention / Treatment
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* Drug: Morphine
* Drug: CG5503 IR
* Drug: CG5503 IR
* Drug: CG5503 IR
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female between 18 and 80 years of age; Scheduled to undergo an abdominal hysterectomy with or without bilateral salpingo-oophorectomy due to uterine leiomyomas, or dysfunctional uterine bleeding or endometrial hyperplasia; Anesthesiological and surgical procedures performed according to protocol; Moderate or severe baseline pain following hysterectomy on a Verbal Rating Scale (VRS) within 6 hours following the last possible application of morphine subcutaneous; Pain following hysterectomy of at least 4 on an 11-point Numeric Rating Scale (NRS) within 6 hours following the last possible application of morphine subcutaneous; American Society of Anesthesiologists (ASA) classification I-III. Exclusion Criteria: Vaginal hysterectomy; Ongoing or known history of painful endometriosis; Known or suspected chronic pelvic pain syndrome; Previous abdominal or pelvic open surgery; History of seizure disorder or epilepsy; History of alcohol or drug abuse; Evidence of active infections that may spread to other areas of the body; severely impaired renal function, moderately or severely impaired hepatic function, Allergy or hypersensitivity to oxycodone, morphine, fentanyl hydromorphone, heparin, or any compound planned to be used during the anesthesia; Serious complication during surgery and up to randomization; Pre-operative use within 12hours prior to surgery or peri-operative use of non-steroidal anti-inflammatory drugs (NSAIDs); Treated regularly with opioid analgesic or non-steroidal anti-inflammatory drugs (NSAIDs) within 30 days prior to screening;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 |
| --- | --- |
| Active Comparator: Morphine<br> | Drug: Morphine<br>* 20 mg IR; 4 - 6 hourly; Total 72 hours<br>|
| Experimental: Tapentadol 50 mg immediate release<br> | Drug: CG5503 IR<br>* 50mg; 4 - 6 hourly; Total 72 hours<br>* Other names: Tapentadol;|
| Experimental: Tapentadol 75 mg immediate release<br> | Drug: CG5503 IR<br>* 75mg; 4 -6 hourly; Total 72 hours<br>* Other names: Tapentadol;|
| Experimental: Tapentadol 100 mg immediate release<br> | Drug: CG5503 IR<br>* 100mg, 4 - 6 hourly; Total 72 hours<br>* Other names: Tapentadol;|
| Placebo Comparator: Matched placebo<br> | Drug: Placebo<br>* 4 - 6 hourly; Total 72 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity. | Pain Intensity assessed at predefined time points over a 24 hour period using an 11-point Numeric Rating Scale (NRS) where a score of zero indicates no pain and a score of ten indicates pain as bad as you can imagine. Differences calculated as [baseline-post baseline] at each predefined time point. The theoretical maximum range of Sum of pain intensity differences (SPID24) is from -240 (indicative of an increase in pain) to 240 (indicative of a decrease in pain, assuming patients start with a baseline value of 10 and all subsequent values will be 0). | Baseline to 24 hours after first intake of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of Pain Intensity Differences Relative to the Baseline Pain Intensity | Pain Intensity assessed at predefined time points over a 48 hour period using an 11-point Numeric Rating Scale (NRS) where a score of zero indicates no pain and a score of ten indicates pain as bad as you can imagine. Differences calculated as [baseline-post baseline] at each predefined time point. The theoretical maximum range of Sum of pain intensity differences (SPID48) is from -480 (indicative of an increase in pain) to 480 (indicative of a decrease in pain, assuming patients start with a baseline value of 10 and all subsequent values will be 0). | Baseline value to 48 hours after first study drug intake. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid, Central acting analgesic, Pain postoperative, Abdomen acute, CG5503 IR, Morphine, Placebo