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, Bianca Rocca, Alberto Tosetto, Denise Soldati, Giovanna Petrucci, Eloise Beggiato, Irene Bertozzi, Silvia Betti, Giuseppe Carli, Monica Carpenedo, Daniele Cattaneo, Viviana Cavalca, Alfredo Dragani, Elena Elli, Guido Finazzi, Alessandra Iurlo, Giuseppe Lanzarone, Laura Lissandrini, Francesca Palandri, Chiara Paoli & 13 others Alessandro Rambaldi, Paola Ranalli, Maria Luigia Randi, Alessandra Ricco, Elena Rossi, Marco Ruggeri, Giorgina Specchia, Andrea Timillero, Linda Turnu, Nicola Vianelli, Alessandro M Vannucchi, Francesco Rodeghiero, Carlo Patrono

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)49
JournalBlood Cancer Journal
Volume8
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

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Essential Thrombocythemia
Thromboxane B2
Aspirin
Serum
Biomarkers
Blood Platelets
Cyclooxygenase 1
Polycythemia Vera
Thromboxane A2
Epoprostenol
Multicenter Studies
Blood Vessels
Placebos
Exercise

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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. / De Stefano, Valerio; Rocca, Bianca; Tosetto, Alberto; Soldati, Denise; Petrucci, Giovanna; Beggiato, Eloise; Bertozzi, Irene; Betti, Silvia; Carli, Giuseppe; Carpenedo, Monica; Cattaneo, Daniele; Cavalca, Viviana; Dragani, Alfredo; Elli, Elena; Finazzi, Guido; Iurlo, Alessandra; Lanzarone, Giuseppe; Lissandrini, Laura; Palandri, Francesca; Paoli, Chiara; Rambaldi, Alessandro; Ranalli, Paola; Randi, Maria Luigia; Ricco, Alessandra; Rossi, Elena; Ruggeri, Marco; Specchia, Giorgina; Timillero, Andrea; Turnu, Linda; Vianelli, Nicola; Vannucchi, Alessandro M; Rodeghiero, Francesco; Patrono, Carlo.

In: Blood Cancer Journal, Vol. 8, No. 6, 01.06.2018, p. 49.

Research output: Contribution to journalArticle

De Stefano, V, Rocca, B, Tosetto, A, Soldati, D, Petrucci, G, Beggiato, E, Bertozzi, I, Betti, S, Carli, G, Carpenedo, M, Cattaneo, D, Cavalca, V, Dragani, A, Elli, E, Finazzi, G, Iurlo, A, Lanzarone, G, Lissandrini, L, Palandri, F, Paoli, C, Rambaldi, A, Ranalli, P, Randi, ML, Ricco, A, Rossi, E, Ruggeri, M, Specchia, G, Timillero, A, Turnu, L, Vianelli, N, Vannucchi, AM, Rodeghiero, F & Patrono, C 2018, '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', Blood Cancer Journal, vol. 8, no. 6, pp. 49. https://doi.org/10.1038/s41408-018-0078-3
De Stefano, Valerio ; Rocca, Bianca ; Tosetto, Alberto ; Soldati, Denise ; Petrucci, Giovanna ; Beggiato, Eloise ; Bertozzi, Irene ; Betti, Silvia ; Carli, Giuseppe ; Carpenedo, Monica ; Cattaneo, Daniele ; Cavalca, Viviana ; Dragani, Alfredo ; Elli, Elena ; Finazzi, Guido ; Iurlo, Alessandra ; Lanzarone, Giuseppe ; Lissandrini, Laura ; Palandri, Francesca ; Paoli, Chiara ; Rambaldi, Alessandro ; Ranalli, Paola ; Randi, Maria Luigia ; Ricco, Alessandra ; Rossi, Elena ; Ruggeri, Marco ; Specchia, Giorgina ; Timillero, Andrea ; Turnu, Linda ; Vianelli, Nicola ; Vannucchi, Alessandro M ; Rodeghiero, Francesco ; Patrono, Carlo. / 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. In: Blood Cancer Journal. 2018 ; Vol. 8, No. 6. pp. 49.
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T2 - Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting

AU - De Stefano, Valerio

AU - Rocca, Bianca

AU - Tosetto, Alberto

AU - Soldati, Denise

AU - Petrucci, Giovanna

AU - Beggiato, Eloise

AU - Bertozzi, Irene

AU - Betti, Silvia

AU - Carli, Giuseppe

AU - Carpenedo, Monica

AU - Cattaneo, Daniele

AU - Cavalca, Viviana

AU - Dragani, Alfredo

AU - Elli, Elena

AU - Finazzi, Guido

AU - Iurlo, Alessandra

AU - Lanzarone, Giuseppe

AU - Lissandrini, Laura

AU - Palandri, Francesca

AU - Paoli, Chiara

AU - Rambaldi, Alessandro

AU - Ranalli, Paola

AU - Randi, Maria Luigia

AU - Ricco, Alessandra

AU - Rossi, Elena

AU - Ruggeri, Marco

AU - Specchia, Giorgina

AU - Timillero, Andrea

AU - Turnu, Linda

AU - Vianelli, Nicola

AU - Vannucchi, Alessandro M

AU - Rodeghiero, Francesco

AU - Patrono, Carlo

PY - 2018/6/1

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N2 - 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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M3 - Article

VL - 8

SP - 49

JO - Blood Cancer Journal

JF - Blood Cancer Journal

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