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Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial

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Abstract

Purpose

Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host–pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shock patients.

Methods

This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began < 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations.

Results

Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was − 0.7 (± 0.85) in the randomized population and − 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points.

Conclusion

No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker.

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Data availability

Sharing of de-identified patient data does not comply with the General Data Protection Regulation (GDPR) in the EU. Therefore, individual, de-identified participant data will currently not be shared. This clinical trial was designed and started before the regulation came into effect. The informed consent form that the participants signed for this study did not address the sharing of individual patient data. Therefore, the authors are currently not allowed to share such data.

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Acknowledgements

We thank Simon Lambden and Jean-Marie Grouin for critical review of this manuscript as well as the data monitoring and data adjudication committee members, Professors Michel Wolff and Jean Chastre. Support of PK NCA calculation and modeling was performed by Calvagone and MnS. Support for third-party writing assistance for this article, furnished by Megan Christian, was provided by Prism Ideas and funded by Inotrem SA.

Funding

This study, and editorial support for the preparation of this manuscript, was funded by Inotrem SA.

Author information

Authors and Affiliations

  1. Medical-Surgical ICU Department and Inserm CIC1435 & UMR1092, CRICS-TRIGGERSEP Network, CHU Limoges, Limoges, France

    Bruno François

  2. Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

    Xavier Wittebole & Pierre-François Laterre

  3. ICU Department, Vall d’Hebron University Hospital, Barcelona, Spain

    Ricard Ferrer

  4. Medical ICU, Cochin Hotel-Dieu, AP-HP, Paris, France

    Jean-Paul Mira

  5. ICU Department, Clinique St. Pierre, Ottignies, Belgium

    Thierry Dugernier

  6. Medical ICU Department, Hospital Central, CHU Nancy, Nancy, France

    Sébastien Gibot

  7. Inserm U1116, Nancy Medical Faculty, Lorraine University, Nancy , France

    Sébastien Gibot

  8. Inotrem SA, Paris, France

    Marc Derive, Aurélie Olivier, Valérie Cuvier, Jean-Jacques Garaud & Margarita Salcedo-Magguilli

  9. Helion Pharma, Schriesheim, Germany

    Stephan Witte

  10. ICU Department, Radboudumc Hospital, Nijmegen, The Netherlands

    Peter Pickkers

  11. ClinBay SPRL, Baisy-Thy, Belgium

    François Vandenhende

  12. ICU Department, Hospital Clínico San Carlos, Madrid, Spain

    Miguel Sánchez

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  1. Bruno François
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Contributions

JJG, SW, MSM, BF, and PFL conceived and designed the study. BF was the Principal investigator. BF, XW, RF, JPM, TD, SG, PP, MS, and PFL collected data. MSM and FV developed analysis tools. MSM, FV, BF, PFL, JJG, SG, MD, VC, and AO analyzed the data. BF, SG, MSM, and PFL wrote the manuscript. All authors reviewed and revised the manuscript.

Corresponding author

Correspondence to Bruno François.

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Conflicts of interest

BF reports personal fees from Inotrem during the conduct of the study, and personal fees from Biomérieux, Aridis, Ashai-Kasai, Polyphor, AM-Pharma, and Ferring outside the submitted work. XW reports fees from Inotrem during the conduct of the study, and fees from AKPA and Ferring outside the submitted work. RF reports personal fees from MSD, Pfizer, Shionogi, Grifols, Toray, and BD outside the submitted work. PFL reports personal fees from Inotrem outside the submitted work. FRV reports personal fees from Inotrem during the conduct of the study. PP reports personal fees from Inotrem during the conduct of the study, and fees from AM-Pharma, EBI, and Ferring outside the submitted work. SW has acted as a consultant to Inotrem. MD and SG hold patent EP2011055519, licensed to Inotrem. MD, AO, VC, JJG, and MSM are employees of Inotrem. JPM, TD, and MS have nothing to disclose.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval of the study protocol and all amendments was granted by the following Ethics Committees: France: Comité de Protection des Personnes Ile de France (initial approval 13th September 2017; 2017-04-02 MS1 RIPH 1°). The Netherlands: Radboud University Medical Centre, Commissie Mensgebonden Onderzoek Regio Arnhem-Nijmegen (initial approval 19th July 2017; 2017-3326), Belgium: Cliniques Universitaires Saint Luc, Comité d’Éthique Hospitalo-Facultaire (initial approval 27th April 2017; 2017/15MAR138) Spain: Hospital Clinico San Carlos, Comité de Ética de la Investigación con Medicamentos (initial approval 31st May 2017; 17/162-R_M).

Informed consent

Written informed consent was obtained from each participant, or authorized representative in case of incapacitated patients, prior to study enrollment.

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François, B., Wittebole, X., Ferrer, R. et al. Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial. Intensive Care Med 46, 1425–1437 (2020). https://doi.org/10.1007/s00134-020-06109-z

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  • DOI: https://doi.org/10.1007/s00134-020-06109-z

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