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.
Détails
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Etat: Public
Version: de l'auteur⸱e
Licence: CC BY 4.0
ID Serval
serval:BIB_851C736F5621
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
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.
Périodique
Critical care
Collaborateur⸱rice⸱s
COMBACTE-MAGNET EVADE Study Group
Contributeur⸱rice⸱s
Joannidis M., Klimscha W., De Waele E., Devriendt J., Huberlant V., Depuydt P., Van Boxstael S., Peric M., Kopic J., Hanauer M., Hruby T., Sramek V., Svoboda P., Vymazal T., Novacek M., Annane D., Mira J.P., Souweine B., Dequin P.F., Meziani F., Stephan F., Nseir S., Gibot S., Schwebel C., Plantefeve G., Diehl J.L., Richard C., Lamer C., Klouche K., Jaber S., Zakynthinos E., Filntisis G., Zakynthinos S., Koutsoukou A., Saroglou G., Nikolaou C., Vlachogianni G., Pnevmatikos I., Mandragos K., Kremer I., Rozgonyi Z.D., Marjanek Z., Martin-Loeches I., Singer P., Van Heerden V., Carmeli Y., Povoa P., Seoane A.A., Moura P., Gonzalez F., Ramirez P., Marti A.T., Roca R.F., Oteiza L., Escudero D., Piacentini E., Vera P., Tamayo L., Gallego MAG, Canas B.S., Figueira I., Leon R., Korten V., Akova M., Wyncoll D., Whitehouse T., Hopkins P., Sim M., Golan Y., Zervos M., Vazquez J., Cherabuddi K., Smulian G., Rouphael N., Welker J., Sims M., Van Duin D., McCarthy T., Polk C.
ISSN
1466-609X (Electronic)
ISSN-L
1364-8535
Statut éditorial
Publié
Date de publication
15/11/2022
Peer-reviewed
Oui
Volume
26
Numéro
1
Pages
355
Langue
anglais
Notes
Publication types: Randomized Controlled Trial ; Clinical Trial, Phase II ; Journal Article
Publication Status: epublish
Publication Status: epublish
Résumé
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.
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.
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.
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.
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.
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.
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.
Mots-clé
Animals, Humans, Adolescent, Pseudomonas aeruginosa, Pseudomonas Infections/drug therapy, Pseudomonas Infections/prevention & control, Respiration, Artificial/adverse effects, Pneumonia, Ventilator-Associated/drug therapy, Double-Blind Method, Intensive Care Units, Antibodies, Monoclonal/therapeutic use, Treatment Outcome, Monoclonal antibody, Pharmacokinetics, Prevention, Pseudomonas aeruginosa ventilator-associated pneumonia, Safety
Pubmed
Web of science
Open Access
Oui
Création de la notice
29/11/2022 10:53
Dernière modification de la notice
19/07/2023 5:55
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