학술논문
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
Document Type
Report
Author
Chastre, Jean; François, Bruno; Bourgeois, Marc; Komnos, Apostolos; Ferrer, Ricard; Rahav, Galia; De Schryver, Nicolas; Lepape, Alain; Koksal, Iftihar; Luyt, Charles-Edouard; Sánchez-García, Miguel; Torres, Antoni; Eggimann, Philippe; Koulenti, Despoina; Holland, Thomas L.; Ali, Omar; Shoemaker, Kathryn; Ren, Pin; Sauser, Julien; Ruzin, Alexey; Tabor, David E.; Akhgar, Ahmad; Wu, Yuling; Jiang, Yu; DiGiandomenico, Antonio; Colbert, Susan; Vandamme, Drieke; Coenjaerts, Frank; Malhotra-Kumar, Surbhi; Timbermont, Leen; Oliver, Antonio; Barraud, Olivier; Bellamy, Terramika; Bonten, Marc; Goossens, Herman; Reisner, Colin; Esser, Mark T.; Jafri, Hasan S.; Joannidis, Michael; Klimscha, Walter; De Waele, Elisabeth; Devriendt, Jacques; Huberlant, Vincent; Depuydt, Pieter; Van Boxstael, Sam; Peric, Mladen; Kopic, Jasminka; Hanauer, Michal; Hruby, Tomas; Sramek, Vladimir; Svoboda, Petr; Vymazal, Tomas; Novacek, Martin; Annane, Djillali; Mira, Jean-Paul; Souweine, Bertrand; Dequin, Pierre-François; Meziani, Ferhat; Stephan, François; Nseir, Saadalla; Gibot, Sebastien; Schwebel, Carole; Plantefeve, Gaetan; Diehl, Jean-Luc; Richard, Christian; Lamer, Christian; Klouche, Kada; Jaber, Samir; Zakynthinos, Epaminondas; Filntisis, Georgios; Zakynthinos, Spyros; Koutsoukou, Antonia; Saroglou, Georgios; Nikolaou, Charikleia; Vlachogianni, Glykeria; Pnevmatikos, Ioannis; Mandragos, Konstantinos; Kremer, Ildiko; Rozgonyi, Zsolt Dezso; Marjanek, Zsuzsa; Martin-Loeches, Ignacio; Singer, Pierre; Van Heerden, Vernon; Carmeli, Yehuda; Povoa, Pedro; Seoane, Antonio Alvarez; Moura, Pedro; Gonzalez, Filipe; Ramirez, Paula; Marti, Antonio Torres; Roca, Ricard Ferrer; Oteiza, Lorena; Escudero, Dolores; Piacentini, Enrique; Vera, Paula; Tamayo, Luis; Gallego, Miguel Angel Gonzalez; Canas, Borja Suberviola; Figueira, Iglesias; Leon, Rafael; Korten, Volkan; Akova, Murat; Wyncoll, Duncan; Whitehouse, Tony; Hopkins, Phil; Sim, Malcolm; Golan, Yoav; Zervos, Marcus; Vazquez, Jose; Cherabuddi, Kartikeya; Smulian, George; Rouphael, Nadine; Welker, James; Sims, Mathew; Van Duin, David; McCarthy, Todd; Polk, Christopher
Source
Critical Care. November 15, 2022, Vol. 26 Issue 1
Subject
Language
English
ISSN
1364-8535
Abstract
Author(s): Jean Chastre[sup.1] , Bruno François[sup.2] , Marc Bourgeois[sup.3] , Apostolos Komnos[sup.4] , Ricard Ferrer[sup.5] , Galia Rahav[sup.6] , Nicolas De Schryver[sup.7] , Alain Lepape[sup.8] , Iftihar Koksal[sup.9] , Charles-Edouard [...]
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 [greater than or equal to] 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) [mu]g/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 [mu]g/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. Keywords: Monoclonal antibody, Prevention, Pharmacokinetics, Pseudomonas aeruginosa ventilator-associated pneumonia, Safety
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 [greater than or equal to] 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) [mu]g/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 [mu]g/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. Keywords: Monoclonal antibody, Prevention, Pharmacokinetics, Pseudomonas aeruginosa ventilator-associated pneumonia, Safety