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

• DOI: 10.1007/s00134-021-06537-5
• Publication Date: 2021-10-05T00:07:40Z
• Authors: Pierre-François L...; Peter Pickkers; Gernot Marx; Xavier Wittebole; Ferhat Meziani; Thierry Dugernier; Vincent Huberlant; Tobias Schuerholz; Bruno François; Jean-Baptiste Las...; Albertus Beishuizen; Haikel Oueslati; Damien Contou; Oscar Hoiting; Jean-Claude Lache...; Benjamin Chousterman; Julien Pottecher; Michael Bauer; Thomas Godet; Mahir Karakas; Julie Helms; Andreas Bergmann; Jens Zimmermann; Kathleen Richter; Oliver Hartmann; Melanie Pars; Alexandre Mebazaa; ; Diego Castanares; Christine Collienne; Ludovic Gèrards; Phillipe Hantson; Virginie Montiel; Caroline Berghe; Marie-France Duja...; Leslie Gielens; Suzanne Renard; Philippe 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 Ducha...; Ludmila Baudrillart; Paul Bourzeix; Alexandra Gay; Céline Prevost; Coralie Chalot; Isabelle Herafa; Perrine Engels; Martin Maëlle; Lila-Fariza Abeud; Laure Berton; Kamile Cerlinskaite; Nicolas Deye; Marie-Celine Four...; Tassadit Hadjam; Alexa Hollinger; Tuija Javanainen; Clement Jourdaine; Matthieu Legrand; Badr Louadah; Arthur Neuschwander; Raphaël Clere-Jehl; Julien Demiselle; Hamid Merdji; Alexandra Monnier; Emmanuelle Mercier; Stefan Kluge; Alexander Zarbock; Arthur R. H. van ...; Wytze Vermeijden; Tom Dormans
• Keywords: Tolerability; Clinical endpoint; Contraindication; SOFA score

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.