Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial

被引:58
作者
Cremer, Paul C. [1 ]
Abbate, Antonio [4 ]
Hudock, Kristin [5 ]
McWilliams, Carla [7 ]
Mehta, Jinesh [8 ]
Chang, Steven Y. [9 ]
Sheng, Calvin C. [1 ]
Van Tassell, Benjamin [4 ]
Bonaventura, Aldo [4 ]
Vecchie, Alessandra [4 ]
Carey, Brenna [5 ,6 ]
Wang, Qiuqing [1 ,2 ]
Wolski, Katherine E. [1 ,2 ]
Rajendram, Prabalini [3 ]
Duggal, Abhijit [3 ]
Wang, Tisha S. [9 ]
Paolini, John F. [10 ]
Trapnell, Bruce C. [5 ,6 ]
机构
[1] Cleveland Clin, Dept Cardiovasc Med, Heart Vascular & Thorac Inst, Cleveland, OH 44106 USA
[2] Cleveland Clin, Coordinating Ctr Clin Res, Cleveland, OH 44106 USA
[3] Cleveland Clin, Dept Pulm Med, Resp Inst, Cleveland, OH 44106 USA
[4] Virginia Commonwealth Univ, Wright Ctr forClin & Translat Res, Richmond, VA USA
[5] Univ Cincinnati, Div Pulm Crit Care & Sleep Med, Div Pulm Biol, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA
[6] Univ Cincinnati, Translat Pulm Sci Ctr, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA
[7] ClevelandClin Florida, Dept Infect Dis, Weston, FL USA
[8] ClevelandClin Florida, Dept Pulm & Crit Care, Weston, FL USA
[9] Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm & Crit Care Med, Los Angeles, CA 90095 USA
[10] Kiniksa Pharmaceut, Lexington, MA USA
关键词
GM-CSF;
D O I
10.1016/S2665-9913(21)00070-9
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background In patients with COVID-19, granulocyte-macrophage colony stimulating factor (GM-CSF) might be a mediator of the hyperactive inflammatory response associated with respiratory failure and death. We aimed to evaluate whether mavrilimumab, a monoclonal antibody to the GM-CSF receptor, would improve outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation. Methods This investigator-initiated, multicentre, double-blind, randomised trial was done at seven hospitals in the USA. Inclusion required hospitalisation, COVID-19 pneumonia, hypoxaemia, and a C-reactive protein concentration of more than 5 mg/dL. Patients were excluded if they required mechanical ventilation. Patients were randomly assigned (1:1) centrally, with stratification by hospital site, to receive mavrilimumab 6 mg/kg as a single intravenous infusion, or placebo. Participants and all clinical and research personnel were masked to treatment assignment. The primary endpoint was the proportion of patients alive and off supplemental oxygen therapy at day 14. The primary outcome and safety were analysed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04399980, NCT04463004, and NCT04492514. Findings Between May 28 and Sept 15, 2020, 40 patients were enrolled and randomly assigned to mavrilimumab (n=21) or placebo (n=19). A trial of 60 patients was planned, but given slow enrolment, the study was stopped early to inform the natural history and potential treatment effect. At day 14, 12 (57%) patients in the mavrilimumab group were alive and off supplemental oxygen therapy compared with nine (47%) patients in the placebo group (odds ratio 1.48 [95% CI 0.43-5.16]; p=0.76). There were no treatment-related deaths, and adverse events were similar between groups. Interpretation There was no significant difference in the proportion of patients alive and off oxygen therapy at day 14, although benefit or harm of mavrilimumab therapy in this patient population remains possible given the wide confidence intervals, and larger trials should be completed. Copyright (C) 2021 Elsevier Ltd. All rights reserved.
引用
收藏
页码:E410 / E418
页数:9
相关论文
共 29 条
[1]   Remdesivir for the Treatment of Covid-19-Final Report [J].
Beigel, John H. ;
Tomashek, Kay M. ;
Dodd, Lori E. ;
Mehta, Aneesh K. ;
Zingman, Barry S. ;
Kalil, Andre C. ;
Hohmann, Elizabeth ;
Chu, Helen Y. ;
Luetkemeyer, Annie ;
Kline, Susan ;
de Castilla, Diego Lopez ;
Finberg, Robert W. ;
Dierberg, Kerry ;
Tapson, Victor ;
Hsieh, Lanny ;
Patterson, Thomas F. ;
Paredes, Roger ;
Sweeney, Daniel A. ;
Short, William R. ;
Touloumi, Giota ;
Lye, David Chien ;
Ohmagari, Norio ;
Oh, Myoung-don ;
Ruiz-Palacios, Guillermo M. ;
Benfield, Thomas ;
Faetkenheuer, Gerd ;
Kortepeter, Mark G. ;
Atmar, Robert L. ;
Creech, C. Buddy ;
Lundgren, Jens ;
Babiker, Abdel G. ;
Pett, Sarah ;
Neaton, James D. ;
Burgess, Timothy H. ;
Bonnett, Tyler ;
Green, Michelle ;
Makowski, Mat ;
Osinusi, Anu ;
Nayak, Seema ;
Lane, H. Clifford .
NEW ENGLAND JOURNAL OF MEDICINE, 2020, 383 (19) :1813-1826
[2]   Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies [J].
Bonaventura, Aldo ;
Vecchie, Alessandra ;
Wang, Tisha S. ;
Lee, Elinor ;
Cremer, Paul C. ;
Carey, Brenna ;
Rajendram, Prabalini ;
Hudock, Kristin M. ;
Korbee, Leslie ;
Van Tassell, Benjamin W. ;
Dagna, Lorenzo ;
Abbate, Antonio .
FRONTIERS IN IMMUNOLOGY, 2020, 11
[3]   Mavrilimumab, a Fully Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Monoclonal Antibody Long-Term Safety and Efficacy in Patients With Rheumatoid Arthritis [J].
Burmester, Gerd R. ;
McInnes, Iain B. ;
Kremer, Joel M. ;
Miranda, Pedro ;
Vencovsky, Jiri ;
Godwood, Alex ;
Albulescu, Marius ;
Michaels, M. Alex ;
Guo, Xiang ;
Close, David ;
Weinblatt, Michael .
ARTHRITIS & RHEUMATOLOGY, 2018, 70 (05) :679-689
[4]   Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study [J].
Burmester, Gerd R. ;
Feist, Eugen ;
Sleeman, Matthew A. ;
Wang, Bing ;
White, Barbara ;
Magrini, Fabio .
ANNALS OF THE RHEUMATIC DISEASES, 2011, 70 (09) :1542-1549
[5]   Pulmonary pharmacodynamics of an anti-GM-CSFR antibody enables therapeutic dosing that limits exposure in the lung [J].
Campbell, Jamie ;
Nys, Josquin ;
Eghobamien, Laura ;
Cohen, E. Suzanne ;
Robinson, Matthew J. ;
Sleeman, Matthew A. .
MABS, 2016, 8 (07) :1398-1406
[6]  
Cid MC, 2020, ACR CONVERGENCE 2020
[7]   GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study [J].
De Luca, Giacomo ;
Cavalli, Giulio ;
Campochiaro, Corrado ;
Della-Torre, Emanuel ;
Angelillo, Piera ;
Tomelleri, Alessandro ;
Boffini, Nicola ;
Tentori, Stefano ;
Mette, Francesca ;
Farina, Nicola ;
Rovere-Querini, Patrizia ;
Ruggeri, Annalisa ;
D'Aliberti, Teresa ;
Scarpellini, Paolo ;
Landoni, Giovanni ;
De Cobelli, Francesco ;
Paolini, John F. ;
Zangrillo, Alberto ;
Tresoldi, Moreno ;
Trapnell, Bruce C. ;
Ciceri, Fabio ;
Dagna, Lorenzo .
LANCET RHEUMATOLOGY, 2020, 2 (08) :E465-E473
[8]  
Gordon AC, 2021, NEW ENGL J MED, V384, P1491, DOI [10.1056/NEJMoa2100433, 10.1056/NEJMc2108482]
[9]   GM-CSF in inflammation and autoimmunity [J].
Hamilton, JA .
TRENDS IN IMMUNOLOGY, 2002, 23 (08) :403-408
[10]  
Horby P, 2021, NEW ENGL J MED, V384, P693, DOI [10.1056/NEJMoa2021436, 10.1056/NEJMoa2022926]