title: Impact of a fixed-dose combination of naproxen and esomeprazole magnesium on serum thromboxane B2 inhibition by low-dose aspirin over 5 days in healthy adults: a phase I, randomized, double-blind, placebo-controlled, noninferiority trial.
abstract: BACKGROUND
  Low-dose aspirin (LDA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are often used concomitantly; however, some NSAIDs may interfere with LDA antiplatelet activity.
  
  
  OBJECTIVE
  We evaluated the impact of coadministered enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg (fixed-dose combination) on LDA-mediated platelet cyclooxygenase (COX)-1 inhibition.
  
  
  METHODS
  In this Phase I, single-center, double-blind, placebo-controlled study, healthy volunteers (50-75 years) received enteric-coated LDA 81 mg once daily (QD) on days 1 to 5 (open-label), then enteric-coated LDA 81 mg QD plus either naproxen/esomeprazole magnesium or placebo twice daily (BID) on days 6 to 10 (randomized). Serum thromboxane B(2) (TXB(2)) inhibition from baseline to day 11 was the primary end point. The primary analysis excluded volunteers with ≤95% inhibition at day 6. Assay sensitivity and noninferiority of naproxen/esomeprazole magnesium versus placebo were concluded if the 90% CI lower limit for percent inhibition of TXB(2) was >90.0% in both treatment groups (prespecified criterion). Tolerability was a secondary end point.
  
  
  RESULTS
  Overall, 42 volunteers were enrolled, 40 randomized, and 32 included in the primary pharmacodynamic analysis (day 6 TXB(2) inhibition ≥95%). Most volunteers (86%) were white, and 57% were female. Mean age was 60 (7) years, and mean body mass index was 26.4 (2.6) kg/m(2). Day 11 mean serum TXB(2) inhibition was 99.1% (90% CI, 98.7-99.6) in the LDA plus placebo group (n = 18) versus 99.6% (90% CI, 99.4-99.8) in the LDA plus naproxen/esomeprazole magnesium group (n = 14). Noninferiority of naproxen/esomeprazole magnesium versus placebo was established (CI lower limit >90.0%). Adverse event (AE) incidence was 40% (n = 8/20) in the LDA plus placebo group and 15% (n = 3/20) in the LDA plus naproxen/esomeprazole magnesium group. No serious AEs or discontinuations due to AEs were observed.
  
  
  CONCLUSIONS
  This pilot investigation suggests that LDA coadministered with naproxen/esomeprazole magnesium is noninferior to LDA alone for platelet COX-1 inhibition, as measured by serum TXB(2) concentration, in healthy volunteers. ClinicalTrials.gov identifier: NCT01094483.
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, Florida 32209, USA. dominick.angiolillo@jax.ufl.edu
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: Clara
authors.initials: C
authors.lastname: Hwang
authors.forename: Catherine
authors.initials: C
authors.lastname: Datto
authors.forename: Bhaloo
authors.initials: B
authors.lastname: Desai
authors.forename: Mark
authors.initials: M
authors.lastname: Sostek
mesh_terms: D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects; D001241:Aspirin / Q000008:administration & dosage* / Q000009:adverse effects; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000097:blood*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D004338:Drug Combinations; D064098:Esomeprazole / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000008:administration & dosage* / Q000009:adverse effects; D010865:Pilot Projects; D010919:Placebos; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D013608:Tablets, Enteric-Coated; D013929:Thromboxane B2 / Q000097:blood*; D013997:Time Factors; D014481:United States
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D010919:Placebos; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D013608:Tablets, Enteric-Coated; D013929:Thromboxane B2; D009288:Naproxen; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D064098:Esomeprazole; D001241:Aspirin