Impact of a Fixed-Dose Combination of Naproxen and Esomeprazole Magnesium on Serum Thromboxane B 2 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