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  • A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentra…

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Intensive care
Protocol
A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2)
  1. Christopher Geven1,
  2. Alice Blet2,3,4,
  3. Matthijs Kox1,
  4. Oliver Hartmann5,
  5. Paul Scigalla5,
  6. Jens Zimmermann5,
  7. Gernot Marx6,
  8. Pierre-François Laterre7,
  9. Alexandre Mebazaa2,3,4,
  10. Peter Pickkers1
  1. 1 Department of Intensive Care Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2 Department of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis—Lariboisière, Paris, France
  3. 3 UMR-S 942, Inserm, Paris, France
  4. 4 Paris Diderot University, Paris, France
  5. 5 Adrenomed AG, Hennigsdorf, Germany
  6. 6 Department of Intensive Care Medicine and Intermediate Care, RWTH University Hospital Aachen, Aachen, Germany
  7. 7 Department of Critical Care Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCL), Brussels, Belgium
  1. Correspondence to Professor Peter Pickkers; peter.pickkers{at}radboudumc.nl

Abstract

Introduction Sepsis remains a major health problem with an increasing incidence, high morbidity and high mortality. Apart from treatment with antibiotics and organ support, no approved specific adjunct therapies currently exist. Adrenomedullin (ADM) is a vasoactive peptide. High plasma concentrations of ADM correlate with worse outcome in sepsis patients. Preclinical work with the non-neutralising ADM-binding antibody adrecizumab showed promising effects in animal models of septic shock, including improved vascular barrier function, reduced vasopressor demand and organ dysfunction and increased survival. Therapeutic use of adrecizumab may therefore improve outcome in critically ill patients with septic shock and high ADM plasma concentrations. Phase I studies in healthy volunteers did not reveal any safety concerns. In this biomarker-guided trial, the safety and efficacy of adrecizumab will be investigated in patients with septic shock.

Methods and analysis We describe a phase II, randomised, double-blind, placebo-controlled, biomarker-guided, proof-of-concept and dose-finding clinical trial in patients with early septic shock and high concentration of circulating ADM. A total of 300 patients will be enrolled at approximately 30 sites within the European Union. Patients are randomised to receive active treatment (2 and 4 mg/kg adrecizumab) or placebo, in a 1:1:2 ratio. Patient selection is guided by clinical parameters, and biomarker-guided by measurement of circulating biologically active ADM concentration at admission. Primary endpoint is safety and tolerability of adrecizumab over a 90-day period. A key secondary endpoint is the Sepsis Severity Index over a 14-day period.

Ethics and dissemination This study is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, the European Medicines Agency guidelines of Good Clinical Practice and all other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal.

Trial registration number NCT03085758; Pre-results.

  • sepsis
  • adrecizumab
  • adrenomedullin
  • septic shock
  • vascular integrity
  • phase Ii clinical trial

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

http://dx.doi.org/10.1136/bmjopen-2018-024475

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    Footnotes

    • 33 GM, P-FL, AM, PP share senior authorship.

    • Patient consent for publication Not required.

    • CG and AB contributed equally.

    • Contributors CG and AB drafted the manuscript. The manuscript was critically reviewed by MK, OH, PS, JZ, GM, P-FL, AM and PP. All authors read and approved the final manuscript for publication.

    • Funding This work was supported by Adrenomed AG (the study sponsor; contact JZ, jzimmermann@adrenomed.com).

    • Competing interests CG and AB received travel reimbursements from Adrenomed AG. MK declares to have no competing interests. OH, PS and JZ are employed by Adrenomed AG. GM received travel reimbursements and consultancy fees from Adrenomed AG. P-FL received travel reimbursements and consultancy fees from Adrenomed AG AM received travel reimbursements from Adrenomed AG. UMR-S 942 Inserm received a research grant from Adrenomed AG. PP received travel reimbursements and consultancy fees from Adrenomed AG. PP institution received a research grant from Adrenomed AG. Adrenomed AG reviewed this manuscript. Adrenomed AG holds patent rights on anti-ADM antibodies.

    • Ethics approval This study is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, the European Medicines Agency guidelines of Good Clinical Practice and all other applicable regulations.

    • Provenance and peer review Not commissioned; externally peer reviewed.