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Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial.

Publication ,  Journal Article
Chastre, J; François, B; Bourgeois, M; Komnos, A; Ferrer, R; Rahav, G; De Schryver, N; Lepape, A; Koksal, I; Luyt, C-E; Sánchez-García, M ...
Published in: Crit Care
November 15, 2022

BACKGROUND: Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) in preventing PA nosocomial pneumonia was assessed in PA-colonised mechanically ventilated subjects. METHODS: EVADE (NCT02696902) was a phase 2, randomised, parallel-group, double-blind, placebo-controlled study in Europe, Turkey, Israel, and the USA. Subjects ≥ 18 years old, mechanically ventilated, tracheally colonised with PA, and without new-onset pneumonia, were randomised (1:1:1) to MEDI3902 500, 1500 mg (single intravenous dose), or placebo. The primary efficacy endpoint was the incidence of nosocomial PA pneumonia through 21 days post-dose in MEDI3902 1500 mg versus placebo, determined by an independent adjudication committee. RESULTS: Even if the initial sample size was not reached because of low recruitment, 188 subjects were randomised (MEDI3902 500/1500 mg: n = 16/87; placebo: n = 85) between 13 April 2016 and 17 October 2019. Out of these, 184 were dosed (MEDI3902 500/1500 mg: n = 16/85; placebo: n = 83), comprising the modified intent-to-treat set. Enrolment in the 500 mg arm was discontinued due to pharmacokinetic data demonstrating low MEDI3902 serum concentrations. Subsequently, enrolled subjects were randomised (1:1) to MEDI3902 1500 mg or placebo. PA pneumonia was confirmed in 22.4% (n = 19/85) of MEDI3902 1500 mg recipients and in 18.1% (n = 15/83) of placebo recipients (relative risk reduction [RRR]: - 23.7%; 80% confidence interval [CI] - 83.8%, 16.8%; p = 0.49). At 21 days post-1500 mg dose, the mean (standard deviation) serum MEDI3902 concentration was 9.46 (7.91) μg/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 μg/mL, a level associated with improved outcome in animal models. Treatment-emergent adverse event incidence was similar between groups. CONCLUSIONS: The bivalent, bispecific monoclonal antibody MEDI3902 (gremubamab) did not reduce PA nosocomial pneumonia incidence in PA-colonised mechanically ventilated subjects. Trial registration Registered on Clinicaltrials.gov ( NCT02696902 ) on 11th February 2016 and on EudraCT ( 2015-001706-34 ) on 7th March 2016.

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Published In

Crit Care

DOI

EISSN

1466-609X

Publication Date

November 15, 2022

Volume

26

Issue

1

Start / End Page

355

Location

England

Related Subject Headings

  • Treatment Outcome
  • Respiration, Artificial
  • Pseudomonas aeruginosa
  • Pseudomonas Infections
  • Pneumonia, Ventilator-Associated
  • Intensive Care Units
  • Humans
  • Emergency & Critical Care Medicine
  • Double-Blind Method
  • Antibodies, Monoclonal
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chastre, J., François, B., Bourgeois, M., Komnos, A., Ferrer, R., Rahav, G., … COMBACTE-MAGNET EVADE Study Group, . (2022). Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial. Crit Care, 26(1), 355. https://doi.org/10.1186/s13054-022-04204-9
Chastre, Jean, Bruno François, Marc Bourgeois, Apostolos Komnos, Ricard Ferrer, Galia Rahav, Nicolas De Schryver, et al. “Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial.Crit Care 26, no. 1 (November 15, 2022): 355. https://doi.org/10.1186/s13054-022-04204-9.
Chastre J, François B, Bourgeois M, Komnos A, Ferrer R, Rahav G, De Schryver N, Lepape A, Koksal I, Luyt C-E, Sánchez-García M, Torres A, Eggimann P, Koulenti D, Holland TL, Ali O, Shoemaker K, Ren P, Sauser J, Ruzin A, Tabor DE, Akhgar A, Wu Y, Jiang Y, DiGiandomenico A, Colbert S, Vandamme D, Coenjaerts F, Malhotra-Kumar S, Timbermont L, Oliver A, Barraud O, Bellamy T, Bonten M, Goossens H, Reisner C, Esser MT, Jafri HS, COMBACTE-MAGNET EVADE Study Group. Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial. Crit Care. 2022 Nov 15;26(1):355.

Published In

Crit Care

DOI

EISSN

1466-609X

Publication Date

November 15, 2022

Volume

26

Issue

1

Start / End Page

355

Location

England

Related Subject Headings

  • Treatment Outcome
  • Respiration, Artificial
  • Pseudomonas aeruginosa
  • Pseudomonas Infections
  • Pneumonia, Ventilator-Associated
  • Intensive Care Units
  • Humans
  • Emergency & Critical Care Medicine
  • Double-Blind Method
  • Antibodies, Monoclonal