Clinical trial NCT00746720: Modulation of the Surgical Inflammatory Response by Etoricoxib
Official title: Modulation of the Surgical Inflammatory Response by Etoricoxib: Peripheral Versus Central
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Pain
Osteoarthritis, Hip
Postoperative Pain
Keywords: hip replacement
osteoarthritis
etoricoxib
pain
cerebrospinal fluid
pharmacokinetics
Lead sponsor: University of Erlangen-Nürnberg Medical School
Sponsor class: OTHER
Collaborators: name: HELIOS Kliniken GmbH
name: Rush University Medical Center
name: Merck Sharp & Dohme LLC
First posted: 2008-09-04
Enrollment: 23
Sex: ALL
Minimum age (years): 55
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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.
timeFrame: within 24 hours post dosing (study part 1) and within 48 hour post dosing (study part 2)
Secondary outcomes:
measure: To determine the CSF (cerebrospinal fluid), plasma and tissue pharmacokinetics of orally administered etoricoxib.
timeFrame: within 24 hours post dosing (study part 1) and within 48 hours post dosing (study part 2)
measure: To correlate the prostaglandin and cytokine response to clinical outcome parameters after hip arthroplasty.
timeFrame: within 4 days post dosing (study part 1 and 2)
measure: 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.
timeFrame: within 4 days post dosing (study part 1 and 2)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: HELIOS Klinikum Berlin
Study officials:
affiliation: University of Erlangen-Nürnberg
name: Kay Brune, MD, PhD
role: STUDY_DIRECTOR
affiliation: Helios Klinikum Berlin-Buch
name: Josef Zacher, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Erlangen-Nürnberg
name: Martin Fromm, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rush University
name: Asokumar Buvanendran, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buvanendran A, Kroin JS, Berger RA, Hallab NJ, Saha C, Negrescu C, Moric M, Caicedo MS, Tuman KJ. Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology. 2006 Mar;104(3):403-10. doi: 10.1097/00000542-200603000-00005.
citation: Renner B, Zacher J, Buvanendran A, Walter G, Strauss J, Brune K. Absorption and distribution of etoricoxib in plasma, CSF, and wound tissue in patients following hip surgery--a pilot study. Naunyn Schmiedebergs Arch Pharmacol. 2010 Feb;381(2):127-36. doi: 10.1007/s00210-009-0482-0. Epub 2010 Jan 6.
citation: Renner B, Walter G, Strauss J, Fromm MF, Zacher J, Brune K. Preoperative administration of etoricoxib in patients undergoing hip replacement causes inhibition of inflammatory mediators and pain relief. Eur J Pain. 2012 Jul;16(6):838-48. doi: 10.1002/j.1532-2149.2011.00062.x. Epub 2011 Dec 19.