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Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial

2021; Springer Science+Business Media; Volume: 47; Issue: 11 Linguagem: Inglês

10.1007/s00134-021-06537-5

1432-1238

Pierre‐François Laterre, Peter Pickkers, Gernot Marx, Xavier Wittebole, Ferhat Meziani, Thierry Dugernier, Vincent Huberlant, Tobias Schuerholz, Bruno François, Jean-Baptiste Lascarrou, Albertus Beishuizen, Haikel Oueslati, Damien Contou, Oscar Hoiting, Jean-Claude Lachérade, Benjamin G. Chousterman, Julien Pottecher, Michael Bauer, Thomas Godet, Mahir Karakas, Julie Helms, Andreas Bergmann, Jens Zimmermann, Kathleen M. Richter, Oliver Hartmann, Melanie Pars, Alexandre Mebazaa, Diego Castanares‐Zapatero, Christine Collienne, Ludovic Gèrards, Phillipe Hantson, Virginie Montiel, Caroline Berghe, M Dujardin, Leslie Gielens, Suzanne Renard, Philippe G. Jorens, Pierre Asfar, Gaëtan Plantefève, Jacques Duranteau, Emmanuel Weiss, Constance Vuillard, Anne-Laure Fedou, Marine Goudelin, Bruno Evrard, Thomas Daix, Arnaud Desachy, Philippe Vignon, Anne-Aurore Duchambon, Ludmila Baudrillart, P Bourzeix, Alexandra Gay, Céline Prevost, Coralie Chalot, Isabelle Herafa, P. Engels, Martin Maëlle, Lila-Fariza Abeud, Laure Berton, Kamilė Čerlinskaitė‐Bajorė, Nicolas Deye, Marie-Céline Fournier, Tassadit Hadjam, Alexa Hollinger, Tuija Javanainen, Clément Jourdaine, Matthieu Legrand, Badr Louadah, Arthur Neuschwander, Raphaël Clère-Jehl, Julien Demiselle, Hamid Merdji, Alexandra Monnier, Emmanuelle Mercier, Stefan Kluge, Alexander Zarbock, Arthur R. H. van Zanten, Wytze Vermeijden, Tom Dormans,

Heart Failure Treatment and Management

Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin. Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality. 301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI −1.93–0.49, p = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18–1.35); p = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53–1.31, log-rank p = 0.44). Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.