NSAIDs vs. Coxibs in the Presence of Aspirin

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

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.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; Rheumatoid Arthritis
• Intervention / Treatment: Drug: celecoxib 200mg capsule; Drug: Aspirin 81mg tablet; Drug: naproxen sodium 550mg tablet

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kevin Bliden, BS, MBA; Phone Number: (703) 776-7702; Email: kevin.bliden@inova.org
• Study Contact Backup: Name: Emiliya Bakalska, BA; Phone Number: (410) 367-2592; Email: emiliya.bakalska@inova.org

Study Locations

• United States
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Recruiting
      • Inova Heart and Vascular Institute
      • Contact: Andrea Fitzgerald, RN, MS; Phone Number: 703-776-3330; Email: andrea.fitzgerald@inova.org
      • Contact: Solomon Yeon, MS; Phone Number: (703) 776-4726; Email: solomon.yeaon@inova.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:Qualified patients should have all 4 main criteria

1. Age 18-75 years of age for patients who regularly use NSAIDs.
2. Age 18-65 years of age for patients who do not regularly use NSAIDs
3. Able to give informed consent

4. 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:

1. Unstable angina, MI, CVA, CABG <3 months from screening visit
2. Planned coronary, cerebrovascular, or peripheral revascularization
3. Undergone major surgery within 3 months prior to screening visit or has planned major surgery during the study period
4. Uncontrolled hypertension (SBP >190, DBP >100 mm Hg) during screening visit
5. Uncontrolled arrhythmia < 3 months from screening visit
6. NYHA class III-IV heart failure or if available, ejection fraction ≤ 35 %
7. Within 6 months prior to screening visit, a history of ACS or hospitalization for heart failure
8. Oral corticosteroid, prednisone (or equivalent) > 20 mg daily
9. Anticoagulation therapy
10. Antiplatelet therapy except for aspirin
11. GI ulceration < 60 days before screening visit
12. GI bleeding, perforation, obstruction < 6 months of screening visit
13. Inflammatory bowel disease, diverticulitis active < 6 months of screening visit
14. AST, ALT, or BUN >2x the upper limit normal (within 30 days prior to screening visit)
15. Creatinine level >1.7 mg/dL in men, 1.5 mg/dL in women (within 30 days prior to screening visit)
16. On fluconazole, methotrexate, or lithium therapy
17. Malignancy < 5 years before screening visit
18. Other known, active, significant GI, hepatic, renal, or coagulation disorders
19. Allergy, allergic-type reactions or hypersensitivity (e.g. asthma, urticaria, etc.) to any of the study medications and its components (i.e. sulfonamides)
20. 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
21. 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
22. Subjects who are legally institutionalized
23. Lactating females or females of childbearing potential except for those who are surgically sterile or postmenopausal-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Inova Health Care Services
• Investigators: Study Director: Kevin Bliden, BS, MBA, Inova Health Care Services

Study record dates

Study Major Dates

• Study Start (Actual): September 22, 2018
• Primary Completion (Anticipated): September 24, 2019
• Study Completion (Anticipated): November 24, 2019

Study Registration Dates

• First Submitted: September 21, 2018
• First Submitted That Met QC Criteria: October 4, 2018
• First Posted (Actual): October 9, 2018

Study Record Updates

• Last Update Posted (Actual): October 9, 2018
• Last Update Submitted That Met QC Criteria: October 4, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Cardiovascular Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Cyclooxygenase 2 Inhibitors; Gout Suppressants; Aspirin; Celecoxib; Naproxen
• Other Study ID Numbers: 17-2915

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No plan to share IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No