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Clinical Trial
. 2018 Jun 1;8(6):49.
doi: 10.1038/s41408-018-0078-3.

The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting

Valerio De Stefano  1 , Bianca Rocca  2 , Alberto Tosetto  3 , Denise Soldati  4 , Giovanna Petrucci  2 , Eloise Beggiato  5 , Irene Bertozzi  6 , Silvia Betti  4 , Giuseppe Carli  3 , Monica Carpenedo  7 , Daniele Cattaneo  8 , Viviana Cavalca  9 , Alfredo Dragani  10 , Elena Elli  7 , Guido Finazzi  11 , Alessandra Iurlo  8 , Giuseppe Lanzarone  5 , Laura Lissandrini  3 , Francesca Palandri  12 , Chiara Paoli  13 , Alessandro Rambaldi  11   14 , Paola Ranalli  10 , Maria Luigia Randi  6 , Alessandra Ricco  15 , Elena Rossi  4 , Marco Ruggeri  3 , Giorgina Specchia  16 , Andrea Timillero  16 , Linda Turnu  9 , Nicola Vianelli  12 , Alessandro M Vannucchi  13 , Francesco Rodeghiero  16 , Carlo Patrono  2
Affiliations
Clinical Trial

The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting

Valerio De Stefano et al. Blood Cancer J. .

Abstract

Once-daily (od), low-dose aspirin (75-100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A2 production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB2, a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB2 as a reliable end point for dose-finding studies of novel aspirin regimens.

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Conflict of interest statement

V.D.S. has received consulting and lecture fees from Amgen, Bayer, Celgene, Novartis, and institutional research grants from Novartis; B.R. has received consulting and lecture fees from Amgen, Bayer, Celgene, Daiichi Sankyo Italia, Novartis, and Sanofi; A.Ra. has received consulting and lecture fees from Amgen, Bristol Mayer Squibb, Celgene, Italfarmaco, Novartis, Pfizer, and Roche; F.P. has received consulting and lecture fees from Novartis; A.M.V. has received consulting and lecture fees from Italfarmaco, Novartis, Shire, and institutional research grants from Novartis; C.P. has received consulting and lecture fees from Amgen, AstraZeneca, Bayer, and GlaxoSmithKline, and institutional research grants from Bayer; he serves as Chairperson of the Scientific Advisory Board of the International Aspirin Foundation. The remaining authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Trial design.
The flow chart depicts the design and phases of the ARES study
Fig. 2
Fig. 2. Individual serum TXB2 values across different ARES centers.
a Individual serum TXB2 values measured in samples obtained from 55 healthy subjects in 11 centers. The lower limit of the normal range is indicated by the horizontal line. b The second serum TXB2 determination in 6 selected centers, with the 3 centers showing out-of-range values in the first set of determinations, and 3 other centers, which had appropriate values and were repeated for assessing data reproducibility. Center numbering is the same in a and b
See this image and copyright information in PMC

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