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
Por:
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 T.L., Ali O., Shoemaker K., Ren P., Sauser J., Ruzin A., Tabor D.E., 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 M.T., Jafri H.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 M.A.G., 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.
Publicada:
1 ene 2022
Resumen:
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. © 2022, The Author(s).
Filiaciones:
Chastre J.:
Service de Médecine Intensive Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne University, 47–83 Bd de l’Hôpital, Paris, 75651, France
François B.:
Réanimation Polyvalente and Inserm CIC 1435 & UMR 1092, CHU, Limoges, France
Bourgeois M.:
AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium
Komnos A.:
General Hospital of Larissa, Larissa, Greece
Ferrer R.:
SODIR-VHIR Research Group, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Rahav G.:
Chaim Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
De Schryver N.:
Clinique Saint-Pierre, Ottignies, Belgium
Lepape A.:
Hospices Civils de Lyon Hôpital Lyon Sud, Lyon, France
Koksal I.:
Faculty of Medicine, Trabzon and Acibadem University Faculty of Medicine, Karadeniz Technical University, Istanbul, Turkey
Luyt C.-E.:
Service de Médecine Intensive Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne University, 47–83 Bd de l’Hôpital, Paris, 75651, France
Sánchez-García M.:
Critical Care Department, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain
Torres A.:
Servei de Pneumologia, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERES, ICREA, Barcelona, Spain
Eggimann P.:
Department of Locomotor Apparatus, Centre Hospitalier Universitaire Vaudois CHUV, Lausanne, Switzerland
Koulenti D.:
The University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
2nd Critical Care Department, Attikon University Hospital, National and Kapodistrian, University of Athens, Athens, Greece
Holland T.L.:
Duke Clinical Research Institute, Durham, NC, United States
Ali O.:
Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD 20878, United States
Shoemaker K.:
Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD 20878, United States
Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
Ren P.:
Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
Sauser J.:
Infection Control Program, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
Ruzin A.:
Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD 20878, United States
Tabor D.E.:
Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD 20878, United States
Akhgar A.:
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
Wu Y.:
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
Jiang Y.:
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
DiGiandomenico A.:
Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD 20878, United States
Colbert S.:
Oncology, US SM&M, AstraZeneca, Wilmington, NC, United States
Vandamme D.:
Inserm CIC 1435, CHU, Limoges, France
Coenjaerts F.:
Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Malhotra-Kumar S.:
Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
Timbermont L.:
Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
Oliver A.:
Servicio de Microbiología y Unidad de Investigación, Hospital Universitari Son Espases, Institut d’Investigació Sanitaria Illes Balears, Palma, Spain
Barraud O.:
INSERM U1092, Centre Hospitalier Universitaire de Limoges, Université Limoges, Limoges, France
Bellamy T.:
Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD 20878, United States
Bonten M.:
Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Julius Center for Health Science and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Goossens H.:
Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
Reisner C.:
Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
DevPro Biopharma, Basking Ridge, NJ, United States
Esser M.T.:
Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD 20878, United States
Jafri H.S.:
Clinical Research and Development, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca Biopharmaceuticals, One MedImmune Way, Gaithersburg, MD 20878, United States
Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
Late-Stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
Marti A.T.:
Servei de Pneumologia, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERES, ICREA, Barcelona, Spain
All Open Access, Gold
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