TY - JOUR
T1 - Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections
T2 - The TANGO II Randomized Clinical Trial
AU - Wunderink, Richard G.
AU - Giamarellos-Bourboulis, Evangelos J.
AU - Rahav, Galia
AU - Mathers, Amy J.
AU - Bassetti, Matteo
AU - Vazquez, Jose Antonio
AU - Cornely, Oliver A.
AU - Solomkin, Joseph
AU - Bhowmick, Tanaya
AU - Bishara, Jihad
AU - Daikos, George L.
AU - Felton, Tim
AU - Furst, Maria Jose Lopez
AU - Kwak, Eun Jeong
AU - Menichetti, Francesco
AU - Oren, Ilana
AU - Alexander, Elizabeth L.
AU - Griffith, David
AU - Lomovskaya, Olga
AU - Loutit, Jeffery
AU - Zhang, Shu
AU - Dudley, Michael N.
AU - Kaye, Keith S.
N1 - Funding Information:
Disclosures. Richard G. Wunderink received consulting fees from The Medicines Company, Evangelos J. Giamarellos-Bourboulis received grants from Abbott CH, Astellas Pharma Europe, Axis Shield, BioMerieux france, Xbiotech, FrameWork 7 program HemoSpec, Horizon2020 Marie-Curie project European Sepsis Academy, InflaRx GmbH Germany, and The Medicines Company, and has served as a consultant to AbbiVie USA, Biotest Germany, InflaRx GmbH Germany, The Medicines Company,XBiotech, and Abbott CH the honorarium for these was paid to the University of Athens, honorarium speaker fees were paid to the University of Athens by Brahms GmbH., Galia Rahav received grants and consulting fees from MSD and Pfizer, and received lecture fees from Pfizer and Astel-las, Amy J. Mathers received grants and consulting fees from The Medicines Company, Matteo Bassetti received lecture and/or consultancy fees from MSD, Pfizer, and Astellas, and received grants from MSD and Pfizer, Oliver A. Cornely received grants from Actelion, Arsanis, Astellas, AstraZenenca,Basilea, Bayer, Cidara, F2G, Gilead, GSK, Leeds University, The Medicines Company, Medpace, Melinta Therapeutics, Merck/MSD, Miltenyl, Pfizer, Rempex, Roche, Sanofi Pasteur, Scynexis, Seres Therapeutics, and has received consultancy fees from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, Matinas, Menarini Ricerche, Merck/MSD, Para-tek Pharmaceuticals, Pfizer, PSI, Scynexis, Seres Therapeutics, Summit, Tetraphase, Vical, IQVIA, and has served on advisory boards for Da Volterra and F2G, Gilead, Merck/MSD, Paratek Pharmaceuticals, and Summit. Joseph Solomkin received consultancy fees from Rempex and The Medicines Company. George L. Daikos received grants from Pfizer, MSD and Gilead, and received consultancy fees from Pfizer, Achao-gen, MSD and Gilead. Tim Felton received consultancy fees from Gilead, GSK and Pfizer. Elizabeth L. Alexander was an employee of The Medicines Company during the study and retains stock on the Medicines Company. Elizabeth L. Alexander’s current affiliation is Nab-riva Therapeutics, King of Prussia, PA, USA. David Griffith was employed by The Medicines Company during the study received fees for a US Government contract HHSO100201400002C, under the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA)., Olga Lomovskaya was employed by The Medicines Company during the study, and holds the patent which covers Vaborbactam; 9296763; Patent: Cyclic boronic acid ester derivatives and therapeutic uses thereof. Jeffery Loutit was an employee and shareholder at The Medicines Company. Michael N. Dudley was employee and shareholder of The Medicines Company. Shu Zhang was an employee of The Medicines Company at the time of the study. Keith S. Kaye received consulting fees from Melinta Therapeutics, Allergan, Merck, and Shinogi, and received grants from Merck. The following authors have nothing to disclose: J. Vazquez, T. Bhowmick, J. Bishara, M. Jose Lopez Furst, E. Jeong Kwak, F. Menichetti, I. Oren.
Funding Information:
Funding. This project has been funded in part by The Medicines Company and the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under Contract No. HHSO100201400002C with Rempex Pharmaceuticals, a wholly-owned subsidiary of The Medicines Company and Agreement no. HHSO100201600026C with The Medicines Company. The funder of this study was responsible for study design and data collection. The funder was also responsible for the funding of the journal’s page processing charges. All coauthors were responsible for data interpretation and writing of this report. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Funding Information:
TANGO II investigators who made this study possible. A full list of TANGO II investigators is provided in the Supplemental Material. We thank Dan White, Elizabeth Morgan, Brian Murphy, and Carrie Messerschmidt for thoughtful contribution to this work. Medical writing and editorial support was provided by Purvi Kobawala Smith of Health and Wellness Partners, Upper Saddle River, NJ through funding by The Medicines Company.
Publisher Copyright:
© 2018, The Author(s).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Introduction: Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem–vaborbactam monotherapy versus best available therapy (BAT) for CRE. Methods: A total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem–vaborbactam (2 g/2 g over 3 h, q8h for 7–14 days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings. Results: Within the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) [95% confidence interval (CI) of difference, 3.3% to 61.3%; P = 0.03)] at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%; P = 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, − 44.7% to 9.3%) for meropenem–vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem–vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk–benefit analyses of composite clinical failure or nephrotoxicity favored meropenem–vaborbactam versus BAT (31.3% [10/32] versus 80.0% [12/15]; 95% CI of difference, − 74.6% to − 22.9%; P < 0.001). Conclusions: Monotherapy with meropenem–vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT. Clinical Trials Registration: NCT02168946. Funding: The Medicines Company.
AB - Introduction: Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem–vaborbactam monotherapy versus best available therapy (BAT) for CRE. Methods: A total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem–vaborbactam (2 g/2 g over 3 h, q8h for 7–14 days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings. Results: Within the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) [95% confidence interval (CI) of difference, 3.3% to 61.3%; P = 0.03)] at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%; P = 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, − 44.7% to 9.3%) for meropenem–vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem–vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk–benefit analyses of composite clinical failure or nephrotoxicity favored meropenem–vaborbactam versus BAT (31.3% [10/32] versus 80.0% [12/15]; 95% CI of difference, − 74.6% to − 22.9%; P < 0.001). Conclusions: Monotherapy with meropenem–vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT. Clinical Trials Registration: NCT02168946. Funding: The Medicines Company.
KW - Best available therapy
KW - Carbapenem-resistant Enterobacteriaceae
KW - Meropenem–vaborbactam
KW - Randomized clinical trial
KW - TANGO II
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U2 - 10.1007/s40121-018-0214-1
DO - 10.1007/s40121-018-0214-1
M3 - Article
AN - SCOPUS:85056120314
VL - 7
SP - 439
EP - 455
JO - Infectious Diseases and Therapy
JF - Infectious Diseases and Therapy
SN - 2193-8229
IS - 4
ER -