• Pierre-François Laterre, Peter Pickkers, Gernot Marx, Xavier Wittebole, Ferhat Meziani, Thierry Dugernier, Vincent Huberlant, Tobias Schuerholz, Bruno François, LascarrouJean-BaptisteJBCHU de Nantes, Médecine Intensive Réanimation, 30 Bd. Jean Monnet, 44093, Nantes Cedex 1, France., Albertus Beishuizen, Haikel Oueslati, Damien Contou, Oscar Hoiting, Jean-Claude Lacherade, Benjamin Chousterman, Julien Pottecher, Michael Bauer, Thomas Godet, Mahir Karakas, Julie Helms, Andreas Bergmann, Jens Zimmermann, Kathleen Richter, Oliver Hartmann, Melanie Pars, Alexandre Mebazaa, and AdrenOSS-2 study participants.
• Cliniques Universitaires Saint-Luc, (UCL Bruxelles), Avenue Hippocrate 10, 1200, Brussels, Belgium.
• Intensive Care Med. 2021 Nov 1; 47 (11): 1284-1294.

PurposeInvestigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin.MethodsPhase-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.Results301 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).ConclusionsOverall, 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.© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.

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