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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2021-10-04

AUTHORS

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 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,

ABSTRACT

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. More... »

PAGES

1284-1294

Journal

TITLE

Intensive Care Medicine

ISSUE

11

VOLUME

47

Author Affiliations

  • Cliniques Universitaires Saint-Luc, (UCL Bruxelles), Avenue Hippocrate 10, 1200, Brussels, Belgium
  • Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands
  • Klinik fur Operative Intensivmedizin und Intermediate Care, Universitätsklinikum Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
  • Critical Care Department, Cliniques Universitaires St Luc, UC Louvain, Avenue Hipporcrate 10, 1200, Brussels, Belgium
  • INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative NanoMedicine (RNM), Fédération de Médecine Translationnelle (FMTS), University of Strasbourg, Strasbourg, France
  • Clinique St. Pierre, Avenue Reine Fabiola 9, 1340, Ottignies, Belgium
  • Intensive Care, CH Jolimont, Hospitalier de Jolimont, Rue Ferrer 159, 7100, Haine Saint Paul, Belgium
  • Klinik und Poliklinik fur Anaesthesiologie und Intensivtherapie, Universitätsmedizin Rostock, Schillingallee 35, 18057, Rostock, Germany
  • Réanimation Polyvalente and Inserm CIC1435 & UMR1092, CHU de Limoges, France
  • CHU de Nantes, Médecine Intensive Réanimation, 30 Bd. Jean Monnet, 44093, Nantes Cedex 1, France
  • Intensive Care Center, Medisch Spectrum Twente, Koningsplein 1, 7512KZ, Enschede, The Netherlands
  • Service d’Anesthésie-Réanimation, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010, Paris, France
  • CH Victor Dupouy, 69 Rue du Lieutenant-Colonel Prud’hon, 95107, Argenteuil Cedex, France
  • Canisius-Wilhelmina-Ziekenhuis (CWZ), Weg door Jonkerbosch 100, 6532 SZ, Nijmegen, The Netherlands
  • CHD-Vendée, Médecine Intensive Réanimation, Boulevard Stéphane Moreau, 85000, La Roche-Sur-Yon, France
  • Université de Paris, U942 Inserm, MASCOT, Hôpitaux Universitaires Saint-Louis- Lariboisière, Fernand-Widal, 2, rue Ambroise-Paré, 75475, Paris Cedex 10, France
  • Fédération de Médecine Translationnelle de Strasbourg, Hôpitaux Universitaires de Strasbourg, Service d’Anesthésie-Réanimation & Médecine Péri-Opératoire-Université de Strasbourg, EA3072, Strasbourg, France
  • Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany
  • Département Anesthésie et Réanimation, CHU de Clermont-Ferrand, Pôle de Médecine Péri-opératoire, Clermont-Ferrand, France
  • Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Faculté de Médecine, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France
  • Adrenomed AG, Neuendorfstr. 15a, 16761, Hennigsdorf, Germany
  • Département d’Anesthésie-Réanimation, Hôpital Lariboisière, 2 Rue A Paré, 75010, Paris, France
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00134-021-06537-5

    DOI

    http://dx.doi.org/10.1007/s00134-021-06537-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1141607168

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/34605947


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