NSAIDs vs. Coxibs in the Presence of Aspirin

Study Overview
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Brief Summary
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The objectives of this single site, randomized, crossover study is to evaluate the pharmacodynamic interactions between aspirin, NSAIDs and Coxibs with respect to platelet function, biomarkers of inflammation and endothelial function.

Detailed Description
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The relative cardiovascular safety of NSAIDs, particularly among patients with cardiovascular disease (CVD) or at higher CVD risk, has generated considerable concern among both patients and physicians because of knowledge gaps in the evidence relative to comparative safety and pharmacodynamic interactions between aspirin and NSAIDs. In the recently reported PRECISION trial, a moderate dose of celecoxib was found to be noninferior to ibuprofen or naproxen with respect to cardiovascular safety in patients with arthritis at increased CVD risk. At this time, no comparative prior data are available analyzing the effects of NSAIDs vs. Coxibs in the presence of aspirin on platelet function, biomarkers of inflammation and endothelial function. Thirty patients with rheumatoid arthritis who are at high cardiovascular (CV) risk or with established CV disease will be enrolled in the study. Patients taking anticoagulant therapy or any other antiplatelet agent other than aspirin will be excluded. Patients will be treated with immediate release 81mg aspirin for 4 weeks in the run-in period followed by randomization to celecoxib (200 mg bid) vs. naproxen sodium (550 mg bid) for 4 weeks and then cross over to the other drug for another 4 weeks. Blood and urine samples will be collected at baseline before the aspirin run in period, 24±4 hr after the last dose of aspirin in the run in period, 24±4 hr after the last dose of the first period study drug and 24±4 hr after the last dose of the second period study drug. Assays for platelet function, biomarkers of inflammation and endothelial function will be performed at these time points.

Official Title
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NSAIDs vs. Coxibs in the Presence of Aspirin: Effects on Platelet Function, Endothelial Function, and Biomarkers of Inflammation in Subjects With Rheumatoid Arthritis and Increased Cardiovascular Risk or Cardiovascular Disease

Conditions
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Rheumatoid Arthritis, Cardiovascular Diseases

Intervention / Treatment
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* Drug: celecoxib 200mg capsule
* Drug: naproxen sodium 550mg tablet
* Drug: Aspirin 81mg tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:Qualified patients should have all 4 main criteria Age 18-75 years of age for patients who regularly use NSAIDs. Age 18-65 years of age for patients who do not regularly use NSAIDs Able to give informed consent Subjects with CVD or increased CV risk. Please see definitions for each criteria below: Increased CV risk (Subjects should have at least 3 of the following) > 55 years of age Hypertension Dyslipidemia (LDL > 160 mg/dL or HDL < 40 mg/dL in females and < 35 mg/dL in males or subjects currently receiving lipid lowering therapy as standard of care (i.e. statin drugs, prescription ω 3-acid ethyl esters, fibrates or prescription niacin [≥1,000 mg/d]) Family history of premature CV disease (MI, angina pectoris, heart failure, cardiac death or coronary revascularization, stroke, carotid endarterectomy, or other arterial surgery or angioplasty for atherosclerotic vascular disease in a parent, grandparent, or sibling with symptom onset or diagnosis before age 55 y for males and 65 y for females) Current smoker Left ventricular hypertrophy Documented ankle brachial index of <0.9 History of microalbuminuria, urine protein-creatinine ratio of >2 CV disease (defined as one of the following): Calcium score of >0 ≥ 50 % occlusion of a coronary artery by angiography ≥ 50 % occlusion of a carotid artery by angiography or ultrasound History of stable angina Symptomatic peripheral arterial disease Prior MI, unstable angina, percutaneous coronary intervention, CABG, TIA, ischemic stroke, carotid endarterectomy, or other arterial surgery or angioplasty, which have occurred > 3 months prior to screening visit Diabetes Mellitus type 1 or 2 (considered a CV disease equivalent). Clinical diagnosis of rheumatoid arthritis, as determined by individual patient and physician, requiring daily treatment with NSAIDs. Exclusion Criteria: Subjects with any of the following criteria will be excluded from this study: Unstable angina, MI, CVA, CABG <3 months from screening visit Planned coronary, cerebrovascular, or peripheral revascularization Undergone major surgery within 3 months prior to screening visit or has planned major surgery during the study period Uncontrolled hypertension (SBP >190, DBP >100 mm Hg) during screening visit Uncontrolled arrhythmia < 3 months from screening visit NYHA class III-IV heart failure or if available, ejection fraction ≤ 35 % Within 6 months prior to screening visit, a history of ACS or hospitalization for heart failure Oral corticosteroid, prednisone (or equivalent) > 20 mg daily Anticoagulation therapy Antiplatelet therapy except for aspirin GI ulceration < 60 days before screening visit GI bleeding, perforation, obstruction < 6 months of screening visit Inflammatory bowel disease, diverticulitis active < 6 months of screening visit AST, ALT, or BUN >2x the upper limit normal (within 30 days prior to screening visit) Creatinine level >1.7 mg/dL in men, 1.5 mg/dL in women (within 30 days prior to screening visit) On fluconazole, methotrexate, or lithium therapy Malignancy < 5 years before screening visit Other known, active, significant GI, hepatic, renal, or coagulation disorders Allergy, allergic-type reactions or hypersensitivity (e.g. asthma, urticaria, etc.) to any of the study medications and its components (i.e. sulfonamides) History of any disease of condition that, in the opinion of the investigator would place the subject at an unacceptable risk to participate in this study Any clinically relevant abnormal findings in physical examination, vital signs, or previous laboratory works that, in the opinion of the investigator, may compromise the safety of the subject to participate Subjects who are legally institutionalized Lactating females or females of childbearing potential except for those who are surgically sterile or postmenopausal-

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Qualified patients will be treated with immediate release 81mg aspirin for 4 weeks in the run-in period followed by randomization to celecoxib (200 mg bid) vs. naproxen sodium (550 mg bid) for 4 weeks and then cross over to the other drug for another 4 weeks. Blood and urine samples will be collected before the aspirin run-in period (baseline), 24±4 hrs after the last dose of aspirin in the run-in period, 24±4 hr after the last dose of the study drug in the first period and 24±4 hr after the last dose of the study drug in the second period. Assays for platelet function, biomarkers of inflammation and endothelial function will be performed at these time points
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ASA and Celecoxib<br>Take celecoxib 200mg capsule twice a day and aspirin 81mg tablet once a day for 4 weeks (after completion of the run-in period) | Drug: celecoxib 200mg capsule<br>* celecoxib 200mg twice a day for 4 weeks<br>* Other names: Celebrex;Drug: Aspirin 81mg tablet<br>* 81mg aspirin for 4 weeks in the run-in period, and for 8 weeks during treatment and crossover period<br>* Other names: Bayer Aspirin;|
| Active Comparator: ASA and Naproxen<br>Take naproxen sodium 550mg tablet twice a day and aspirin 81mg tablet once a day (after completion of the run-in period) | Drug: naproxen sodium 550mg tablet<br>* naproxen sodium 550mg twice a day for 4 weeks<br>* Other names: Naprosyn;Drug: Aspirin 81mg tablet<br>* 81mg aspirin for 4 weeks in the run-in period, and for 8 weeks during treatment and crossover period<br>* Other names: Bayer Aspirin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet aggregation | Change in platelet aggregation by light transmittance aggregometry between treatment groups | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum TxB2 | Changes in serum TxB2 between treatment groups | 12 weeks | 
| Urine thromboxane | Changes in urine thromboxane between treatment groups | 12 weeks | 
| Urine 8 iso prostaglandin | Changes in urine 8 iso prostaglandin between treatment groups | 12 weeks | 
| Endothelial function by EndoPAT | Changes in endothelial function by EndoPAT (Endothelial Peripheral Arterial Tone) between treatment groups | 12 weeks | 
| Soluble markers of circulating adhesion molecules (VCAM, ICAM). | Changes in soluble markers of circulating adhesion molecules (VCAM, and ICAM) between treatment groups | 12 weeks | 
| hsCRP | Changes in hsCRP between treatment groups | 12 weeks | 
| Oxidized LDL | Changes in Oxidized LDL between treatment groups | 12 weeks |