Modulation of the Surgical Inflammatory Response by Etoricoxib

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to test the hypothesis that orally administered etoricoxib (COX-2) modulates prostaglandin and cytokine synthesis in the central nervous system (CNS) and in the periphery in surgical patients and thus reduces pain and suffering.

Detailed Description
-----------------
This study will be a multiple centre, double-blind, placebo-controlled, randomized, parallel group study conducted in male and female adult patients undergoing elective primary single hip arthroplasty. In part 1 of the study 12 patients will be enrolled in the study and will be administrated 120 mg Etoricoxib or placebo orally on day one post surgery. The results from part 1 should help to adjust sampling time points (for blood, cerebrospinal fluid and hip drain fluid) if necessary. In part 2 of the study 40 patients will be enrolled and should receive 120 mg etoricoxib or placebo two hours before and 24 hours after surgery. Primary end points will be the inflammatory mediators on peripheral and central levels. After surgical manipulation we expect increased mediators on both sides. It will be investigated if the medication could reduce the mediators compared to placebo and if the effect is related to pharmacokinetic parameters.

Official Title
-----------------
Modulation of the Surgical Inflammatory Response by Etoricoxib: Peripheral Versus Central

Conditions
-----------------
Pain, Osteoarthritis, Hip, Postoperative Pain

Intervention / Treatment
-----------------
* Drug: Etoricoxib 60 mg
* Drug: Placebo for Etoricoxib 60 mg
* Drug: Etoricoxib 60 mg
* Drug: Placebo for Etoricoxib 60 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject undergoing elective primary single hip arthroplasty Subject diagnosed with Osteoarthritis / arthrosis Subject has not taken non-steroidal anti-inflammatory drugs within 4 of their terminal half life times prior to enrollment Subject capable of understanding and cooperating with the requirements of the study Exclusion Criteria: Patients with renal insufficiency (serum creatinine >1.5 mg/dl) Recent major trauma or systemic infection (within 3 months) Use of corticosteroid medication or chronic opioids (within 3 months) Any other condition likely to affect prostaglandin and cytokine levels Participation in another clinical study or receipt of an investigational drug within 30 days Hypersensitivity to any component of the etoricoxib and/or placebo tablets Uncontrolled hypertension defined as systolic blood pressure >140 mm Hg and diastolic pressure >90 mm Hg at rest after two repeated measurements Congestive heart failure (NYHA II-IV) Cerebrovascular disease Established ischemic heart disease (including patients who have recently undergone coronary artery bypass graft surgery or angioplasty) Patients with any kind or severity of cirrhosis of the liver or cholestasis or elevated liver function enzymes (ALT or AST 3 fold) as a sign of clinical significant liver malfunction (corresponds to any Child-Pugh-Score ≥5) Patients who have developed signs of asthma, acute rhinitis, nasal polyps, angioneurotic oedema or urticaria following the administration of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) Pregnancy and lactation Patients with active peptic ulcerations or active gastro-intestinal (GI) bleeding Inflammatory bowel disease Recent history (within the last year) of alcohol or other substance abuse An employee of the sponsor or study site Any neurological syndrome or any other condition leading to contra-indication to spinal anesthesia

Ages Eligible for Study
-----------------
Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A, 1<br>Study part 1 (n = 8) | Drug: Etoricoxib 60 mg<br>* film coated tablet 60 mg (orally), 120 mg (= 2 tablets a 60 mg) once daily, on day one post surgery<br>* Other names: MK0663;|
| Placebo Comparator: A, 2<br>Study part 1 (n = 4) | Drug: Placebo for Etoricoxib 60 mg<br>* film coated tablet (orally), two tablets once daily, on day one post surgery<br>* Other names: Matching Placebo;|
| Experimental: B, 1<br>Study part 2 (n = 20) | Drug: Etoricoxib 60 mg<br>* film coated tablet (orally), 120 mg (= 2 tablets a 60 mg) once daily, two hours before and 24 hours after surgery<br>* Other names: MK0663;|
| Placebo Comparator: B, 2<br>Study part 2 (n = 20) | Drug: Placebo for Etoricoxib 60 mg<br>* film coated tablet (orally), 2 tablets once daily, two hours before and 24 hours after surgery<br>* Other names: Matching Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To test the hypothesis that orally administered etoricoxib (COX-2 inhibitor) modulates prostaglandin and cytokine synthesis in the central nervous system (CNS) and in the periphery in surgical patients. |  | within 24 hours post dosing (study part 1) and within 48 hour post dosing (study part 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the CSF (cerebrospinal fluid), plasma and tissue pharmacokinetics of orally administered etoricoxib. |  | within 24 hours post dosing (study part 1) and within 48 hours post dosing (study part 2) | 
| To correlate the prostaglandin and cytokine response to clinical outcome parameters after hip arthroplasty. |  | within 4 days post dosing (study part 1 and 2) | 
| To assess the safety (via clinical laboratory tests and adverse events) of a single dose of 120 mg Etoricoxib for one day (Part1) or for two days (Part2) and placebo. |  | within 4 days post dosing (study part 1 and 2) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hip replacement, osteoarthritis, etoricoxib, pain, cerebrospinal fluid, pharmacokinetics