Study of MK-0663/Etoricoxib in Postorthopedic Knee Replacement Surgery Pain (MK-0663-098)

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy and safety of Etoricoxib compared to placebo and ibuprofen in the treatment of postoperative pain associated with unilateral total knee replacement surgery. The hypotheses for this study were that the average pain intensity difference (at rest) in participants treated with Etoricoxib (120 mg, 90 mg) is superior to placebo, the average total daily dose of morphine in participants treated with Etoricoxib (120 mg, 90 mg) is less than in participants treated with placebo, and that Etoricoxib (120 mg, 90 mg) will be generally safe and well tolerated by participants treated for pain following total knee replacement orthopedic surgery.

Official Title
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A Phase III Randomized, Double-Blind, Placebo- and Active-Comparator-Controlled, Multiple-Dose, Clinical Trial to Study the Safety and Efficacy of MK0663/Etoricoxib and Ibuprofen in the Treatment of Postorthopedic Knee Replacement Surgery Pain

Conditions
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Pain, Postoperative

Intervention / Treatment
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* Drug: Etoricoxib 90 mg
* Drug: Etoricoxib 120 mg
* Drug: Ibuprofen 600 mg
* Drug: Matching Placebo for Etoricoxib 120 mg
* Drug: Matching Placebo for Etoricoxib 90 mg
* Drug: Matching Placebo for Ibuprofen
* Drug: Morphine
* Drug: Oxycodone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Is in generally good health and is scheduled to have a total knee replacement Exclusion Criteria: Is allergic, intolerant to, or has a history of a significant clinical or laboratory adverse experience associated with etoricoxib or other cyclooxygenase-2 (COX-2) inhibitors/non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen, morphine, or oxycodone, or has hypersensitivity to aspirin, or other NSAIDs Has uncontrolled hypertension Is currently a user of any illicit drugs, or has a history of drug or alcohol abuse within the past 5 years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etoricoxib 90 mg<br>Participants received etoricoxib 90 mg once daily, matching placebo to etoricoxib 120 mg once daily, and matching placebo to ibuprofen 600 mg every 8 hours for 7 days. | Drug: Etoricoxib 90 mg<br>* One 90 mg tablet once daily<br>* Other names: MK-0663;Drug: Matching Placebo for Etoricoxib 120 mg<br>* Two tablets once daily<br>Drug: Matching Placebo for Ibuprofen<br>* One tablet three times daily<br>Drug: Morphine<br>* As needed via patient-controlled analgesia (PCA) device or as a bolus intravenous injection<br>Drug: Oxycodone<br>* 5 mg as needed<br>|
| Experimental: Etoricoxib 120 mg<br>Participants received etoricoxib 120 mg once daily, matching placebo to etoricoxib 90 mg once daily, and matching placebo to ibuprofen 600 mg every 8 hours for 7 days. | Drug: Etoricoxib 120 mg<br>* Two 60 mg tablets once daily<br>* Other names: MK-0663;Drug: Matching Placebo for Etoricoxib 90 mg<br>* One tablet once daily<br>Drug: Matching Placebo for Ibuprofen<br>* One tablet three times daily<br>Drug: Morphine<br>* As needed via patient-controlled analgesia (PCA) device or as a bolus intravenous injection<br>Drug: Oxycodone<br>* 5 mg as needed<br>|
| Active Comparator: Ibuprofen 1800 mg<br>Participants received ibuprofen 600 mg every 8 hours, matching placebo to etoricoxib 120 mg once daily, and matching placebo to etoricoxib 90 mg once daily for 7 days. | Drug: Ibuprofen 600 mg<br>* One tablet three times daily<br>Drug: Matching Placebo for Etoricoxib 120 mg<br>* Two tablets once daily<br>Drug: Matching Placebo for Etoricoxib 90 mg<br>* One tablet once daily<br>Drug: Morphine<br>* As needed via patient-controlled analgesia (PCA) device or as a bolus intravenous injection<br>Drug: Oxycodone<br>* 5 mg as needed<br>|
| Placebo Comparator: Placebo<br>Participants received matching placebo to etoricoxib 90 mg and matching placebo to etoricoxib 120 mg once daily, and matching placebo to ibuprofen every 8 hours for 7 days. | Drug: Matching Placebo for Etoricoxib 120 mg<br>* Two tablets once daily<br>Drug: Matching Placebo for Etoricoxib 90 mg<br>* One tablet once daily<br>Drug: Matching Placebo for Ibuprofen<br>* One tablet three times daily<br>Drug: Morphine<br>* As needed via patient-controlled analgesia (PCA) device or as a bolus intravenous injection<br>Drug: Oxycodone<br>* 5 mg as needed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change From Baseline for Pain Intensity at Rest Over Days 1 to 3 (Etoricoxib vs. Placebo) | The pain intensity difference was measured at rest over Days 1 through 3 in patients treated with etoricoxib (120 mg, 90 mg) compared to placebo for the treatment of pain following total knee replacement orthopedic surgery. Pain intensity difference at rest was measured on a numerical rating scale (NRS) from 0 - 10 points (0=no pain, to 10=pain as bad as you can imagine). Comparison to placebo was conducted in a step-down manner (the 90-mg dose was evaluated only if the null hypotheses for co-primary endpoints [Pain Intensity Difference (PID) and Morphine] 120-mg doses were rejected). The primary analyses for change from baseline in average pain intensity at rest over Days 1 to 3 was performed using the longitudinal data analysis (LDA) method with the terms for baseline pain intensity (moderate or severe), type of anesthesia (spinal or general), treatment, day, and the interaction of day by treatment. | Baseline and Days 1-3 | 
| Average Total Daily Dose of Postoperative Morphine Over Days 1 to 3 (Etoricoxib vs. Placebo) | The average total dose of morphine was assessed when participant received etoricoxib 120 milligram(mg)/90 mg compared to placebo. Opioids taken were converted to mg morphine equivalents according to the following conventions: 1 mg morphine sulphate=1 mg morphine,1 mg morphine hydrochloride=1.17 mg morphine. A 5 mg oxycodone tablet=2.5 mg morphine,12.5 mg meperidine =1.67 mg morphine. Least-squares mean back-transformed; estimate obtained from longitudinal analysis of variance (ANOVA) model on log-transformed morphine dose with terms for baseline pain intensity(moderate or severe),type of anesthesia (spinal, general), treatment, day, and the interaction of day by treatment. | Days 1-3 | 
| Percentage of Participants With at Least One Adverse Event of Congestive Heart Failure, Pulmonary Edema, or Cardiac Failure | An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study product, is also an AE. | Up to 21 days | 
| Percentage of Participants With at Least One Edema-Related AE | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study product, is also an AE. Edema is swelling caused by excess fluid trapped in body tissues. | Up to 21 days | 
| Percentage of Participants With at Least One Hypertension-Related AE | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study product, is also an AE. | Up to 21 days | 
| Percentage of Participants With at Least One Opioid-Related AE | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study product, is also an AE. Opioid-related AEs include nausea, vomiting, constipation, somnolence, respiratory depression, urinary retention and ileus. | Up to 21 days | 
| Percentage of Participants Who Discontinued Study Drug Due to an AE | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study product, is also an AE. | Up to 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change From Baseline for Pain Intensity at Rest Over Days 1 to 3 (Etoricoxib vs. Ibuprofen) | The pain intensity difference was measured at rest over Days 1 through 3 in participants treated with etoricoxib (120 mg, 90 mg) compared to ibuprofen for the treatment of pain following total knee replacement orthopedic surgery. Pain intensity difference at rest was measured on a numerical rating scale (NRS) from 0 - 10 points (0=no pain, to 10=pain as bad as you can imagine). Comparison to ibuprofen was conducted in a step-down manner (the 90-mg dose was evaluated only if the null hypotheses for co-primary endpoints [Pain Intensity Difference (PID) and morphine] 120-mg doses were rejected). The primary analyses for change from baseline in average pain intensity at rest over Days 1 to 3 was performed using the longitudinal data analysis (LDA) method with the terms for baseline pain intensity (moderate or severe), type of anesthesia (spinal or general), treatment, day, and the interaction of day by treatment. | Baseline and Days 1-3 | 
| Average Total Daily Dose of Postoperative Morphine Over Days 1 to 3 (Etoricoxib vs. Ibuprofen) | The difference in average total daily dose of morphine used over Days 1 through 3 between participants treated with etoricoxib (120 mg, 90 mg) or ibuprofen 1800 mg (administered as 600 mg three times daily, every 8 hours) in the treatment of pain following total knee replacement orthopedic surgery was assessed. Opioids taken were converted to mg morphine equivalents according to the following conventions:1 mg morphine sulphate = 1 mg morphine, 1 mg morphine hydrochloride = 1.17 mg morphine. A 5 mg oxycodone tablet = 2.5 mg morphine,12.5 mg meperidine = 1.67 mg morphine. | Days 1-3 |