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