Tixagevimab-cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase atrial

被引：68

作者：

Holland, Thomas L. ^{[1
]}

Ginde, Adit A. ^{[2
]}

Paredes, Roger ^{[3
,4
]}

Murray, Thomas A. ^{[5
]}

Engen, Nicole ^{[5
]}

Grandits, Greg ^{[5
]}

Vekstein, Andrew ^{[6
]}

Ivey, Noel ^{[7
]}

Mourad, Ahmad ^{[8
]}

Sandkovsky, Uriel ^{[9
]}

Gottlieb, Robert L. ^{[10
,11
,12
]}

Berhe, Mezgebe ^{[13
]}

Jain, Mamta K. ^{[14
,15
]}

Marines-Price, Rubria ^{[14
,15
]}

Agbor, Barbine Tchamba Agbor ^{[14
,15
]}

Mateu, Lourdes ^{[16
]}

Espana-Cueto, Sergio ^{[3
]}

Llados, Gemma ^{[3
]}

Mylonakis, Eleftherios ^{[17
,18
]}

Rogers, Ralph ^{[17
,18
]}

Shehadeh, Fadi ^{[17
]}

Filbin, Michael R. ^{[19
]}

Hibbert, Kathryn A. ^{[20
]}

Kim, Kami ^{[21
]}

Tran, Thanh ^{[22
]}

Morris, Peter E. ^{[23
]}

Cassity, Evan P. ^{[23
]}

Trautner, Barbara ^{[24
]}

Pandit, Lavannya M. ^{[24
]}

Knowlton, Kirk U. ^{[25
]}

Leither, Lindsay ^{[26
]}

Matthay, Michael A. ^{[27
,28
]}

Rogers, Angela J. ^{[29
]}

Drake, Wonder ^{[30
]}

Jones, Beatrice ^{[31
]}

Poulakou, Garyfallia ^{[32
]}

Syrigos, Konstantinos N. ^{[32
]}

Fernandez-Cruz, Eduardo ^{[33
]}

Di Natale, Marisa ^{[33
]}

Almasri, Eyad ^{[34
]}

Balerdi-Sarasola, Leire ^{[35
]}

Bhagani, Sanjay R. ^{[36
]}

Boyle, Katherine L. ^{[37
]}

Casey, Jonathan D. ^{[38
]}

Chen, Peter ^{[39
]}

Douin, David J. ^{[40
]}

Files, D. Clark ^{[41
]}

Gunthard, Huldrych F. ^{[42
,43
]}

Hite, R. Duncan ^{[44
]}

Hyzy, Robert C. ^{[45
]}

机构：

[1] Duke Univ, Div Infect Dis, Durham, NC USA

[2] Univ Colorado, Dept Emergency Med, Sch Med, Aurora, CO 80045 USA

[3] Hosp Badalona Germans Trias & Pujol, Infect Dis Dept, Catalonia, Spain

[4] Hosp Badalona Germans Trias & Pujol, irsiCaixa AIDS Res Inst, Catalonia, Spain

[5] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA

[6] Duke Univ, Med Ctr, Dept Surg, Div Cardiovasc & Thorac Surg, Durham, NC 27710 USA

[7] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[8] Duke Univ, Med Ctr, Div Infect Dis, Durham, NC USA

[9] Baylor Univ, Med Ctr, Div Infect Dis, Dallas, TX USA

[10] Baylor Univ, Med Ctr, Ctr Adv Heart & Lung Dis, Dallas, TX USA

[11] Baylor Heart & Vasc Hosp, Dallas, TX USA

[12] Heart Hosp Plano, Baylor Scott & White, Plano, TX USA

[13] Baylor Univ, Med Ctr, Dallas, TX USA

[14] UT Southwestern Med Ctr, Div Infect Dis & Geog Med, Dept Internal Med, Dallas, TX USA

[15] Parkland Hlth & Hosp Syst, Dallas, TX USA

[16] Hosp Univ Gennans Trias & Pujol, Infect Dis Dept, Catalonia, Spain

[17] Rhode Isl Hosp, Div Infect Dis, Providence, RI USA

[18] Brown Univ, Miriam Hosp, Alpert Med Sch, Providence, RI 02912 USA

[19] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA

[20] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA

[21] Univ S Florida, Div Infect Dis & Int Med, Global Emerging Dis Inst, Tampa Gen Hosp, Tampa, FL 33620 USA

[22] Univ S Florida, Div Infect Dis & Int Med, Tampa, FL 33620 USA

[23] Univ Kentucky, Lexington, KY USA

[24] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA

[25] Intermt Med Ctr, Cardiovasc Dept, Salt Lake City, UT USA

[26] Intermt Med Ctr, Salt Lake City, UT USA

[27] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Med, San Francisco, CA 94143 USA

[28] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Anesthesia, San Francisco, CA 94143 USA

[29] Stanford Univ, Div Pulm Allergy & Crit Care Med, Stanford, CA 94305 USA

[30] Vanderbilt Univ, Sch Med, VA Tennessee Valley Healthcare Syst, Nashville Campus, Nashville, TN 37212 USA

[31] VA Tennessee Valley Healthcare Syst, Nashville Campus, Nashville, TN USA

[32] Natl & Kapodistrian Univ Athens, Sotiria Gen Hosp, Athens, Greece

[33] Hosp Gen Univ Gregorio Maranon, Dept Inmunol Clin, Inst Invest Sanitatia Gregorio Maranon, Madrid, Spain

[34] Univ Calif San Francisco, Fresno MEP, Pulm & Crit Care Div, Fresno, CA USA

[35] Hosp Clin Barcelona IS Global, Barcelona, Spain

[36] Royal Free Hosp NHS Fdn Trust, London, England

[37] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[38] Vanderbilt Univ, Med Ctr, Div Allergy Pulm & Crit Care Med, Nashville, TN USA

[39] Cedars Sinai Med Ctr, Div Pulm & Crit Care Med, Los Angeles, CA 90048 USA

[40] Univ Colorado, Sch Med, Dept Anesthesiol, Aurora, CO 80045 USA

[41] Wake Forest Baptist Hlth, Sect Pulm Crit Care Allergy & Immunol Dis, Winston Salem, NC USA

[42] Univ Hosp Zurich, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland

[43] Univ Zurich, Inst Med Virol, Zurich, Switzerland

[44] Univ Cincinnati, Coll Med, Div Pulm Crit Care & Sleep Med, Cincinnati, OH USA

[45] Univ Michigan, Div Pulm & Crit Care, Ann Arbor, MI 48109 USA

[46] Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland, OR 97201 USA

[47] Masaka Reg Referral Hosp, Masaka, Uganda

[48] Gulu Reg Referral & Lospital, Gulu, Uganda

[49] Makerere Univ, Lung Inst, Kampala, Uganda

[50] Strengthening Inst Capac Res Adm SICRA, Kampala, Uganda

来源：

LANCET RESPIRATORY MEDICINE | 2022年 / 10卷 / 10期

基金：

美国国家卫生研究院;

关键词：

STRUCTURAL-CHARACTERIZATION;

D O I：

10.1016/S2213-2600(22)00215-6

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Background Tixagevimab-cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab-cilgavimab versus placebo, in patients receiving remdesivir and other standard care. Methods In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg-cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab-cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing. Findings From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab-cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab-cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1.08 [95% CI 0.97-1.20]; p=0.21). Results were similar in the seronegative subgroup (RRR 1.14 [0.97-1.34]; p=0.13). Mortality was lower in the tixagevimabcilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0.70 [95% CI 0.50-0.97]; p=0.032). The composite safety outcome occurred in 178 (25%) tixagevimab-cilgavimab and 212 (30%) placebo group participants (HR 0.83 [0.68-1.01]; p=0.059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab-cilgavimab group and 38 (5%) in the placebo group. Interpretation Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab-cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower.

引用

页码：972 / 984

页数：13

共 34 条

[1] A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19
Lundgren J.D.
Grund B.
Barkauskas C.E.
Holland T.L.
Gottlieb R.L.
Sandkovsky U.
Brown S.M.
Knowlton K.U.
Self W.H.
Files D.C.
Jain M.K.
Benfield T.
Bowdish M.E.
Leshnower B.G.
Baker J.V.
Jensen J.-U.
Gardner E.M.
Ginde A.A.
Harris E.S.
Johansen I.S.
Markowitz N.
Matthay M.A.
Østergaard L.
Chang C.C.
Davey V.J.
Goodman A.
Higgs E.S.
Murray D.D.
Murray T.A.
Paredes R.
Parmar M.K.B.
Phillips A.N.
Reilly C.
Sharma S.
Dewar R.L.
Teitelbaum M.
Wentworth D.
Cao H.
Klekotka P.
Babiker A.G.
Gelijns A.C.
Kan V.L.
Polizzotto M.N.
Thompson B.T.
Lane H.C.
Neaton J.D.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2021, 384 (10) : 905 - 914
[2] Remdesivir for the Treatment of Covid-19-Final Report
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
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2020, 383 (19) : 1813 - 1826
[3] Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies
Bruel, Timothee
Hadjadj, Jerome
Maes, Piet
Planas, Delphine
Seve, Aymeric
Staropoli, Isabelle
Guivel-Benhassine, Florence
Porrot, Francoise
Bolland, William-Henry
Nguyen, Yann
Casadevall, Marion
Charre, Caroline
Pere, Helene
Veyer, David
Prot, Matthieu
Baidaliuk, Artem
Cuypers, Lize
Planchais, Cyril
Mouquet, Hugo
Baele, Guy
Mouthon, Luc
Hocqueloux, Laurent
Simon-Loriere, Etienne
Andre, Emmanuel
Terrier, Benjamin
Prazuck, Thierry
Schwartz, Olivier
[J]. NATURE MEDICINE, 2022, 28 (06) : 1297 - +
[4] Cameroni E, 2022, NATURE, V602, P664, DOI [10.1038/s41586-021-04386-2, 10.1101/2021.12.12.472269]
[5] Cohen MS, 2021, JAMA-J AM MED ASSOC, V326, P46, DOI [10.1001/jama.2021.8828, 10.1001/jama.2021.88282021.]
[6] Antibody evasion by the P.1 strain of SARS-CoV-2
Dejnirattisai, Wanwisa
Zhou, Daming
Supasa, Piyada
Liu, Chang
Mentzer, Alexander J.
Ginn, Helen M.
Zhao, Yuguang
Duyvesteyn, Helen M. E.
Tuekprakhon, Aekkachai
Nutalai, Rungtiwa
Wang, Beibei
Lopez-Camacho, Cesar
Slon-Campos, Jose
Walter, Thomas S.
Skelly, Donal
Clemens, Sue Ann Costa
Naveca, Felipe Gomes
Nascimento, Valdinete
Nascimento, Fernanda
da Costa, Cristiano Fernandes
Resende, Paola Cristina
Pauvolid-Correa, Alex
Siqueira, Marilda M.
Dold, Christina
Levin, Robert
Dong, Tao
Pollard, Andrew J.
Knight, Julian C.
Crook, Derrick
Lambe, Teresa
Clutterbuck, Elizabeth
Bibi, Sagida
Flaxman, Amy
Bittaye, Mustapha
Belij-Rammerstorfer, Sandra
Gilbert, Sarah C.
Carroll, Miles W.
Klenerman, Paul
Barnes, Eleanor
Dunachie, Susanna J.
Paterson, Neil G.
Williams, Mark A.
Hall, David R.
Hulswit, Ruben J. G.
Bowden, Thomas A.
Fry, Elizabeth E.
Mongkolsapaya, Juthathip
Ren, Jingshan
Stuart, David, I
Screaton, Gavin R.
[J]. CELL, 2021, 184 (11) : 2939 - +
[7] Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail
Dong, Jinhui
Zost, Seth J.
Greaney, Allison J.
Starr, Tyler N.
Dingens, Adam S.
Chen, Elaine C.
Chen, Rita E.
Case, James Brett
Sutton, Rachel E.
Gilchuk, Pavlo
Rodriguez, Jessica
Armstrong, Erica
Gainza, Christopher
Nargi, Rachel S.
Binshtein, Elad
Xie, Xuping
Zhang, Xianwen
Shi, Pei-Yong
Logue, James
Weston, Stuart
McGrath, Marisa E.
Frieman, Matthew B.
Brady, Tyler
Tuffy, Kevin M.
Bright, Helen
Loo, Yueh-Ming
McTamney, Patrick M.
Esser, Mark T.
Carnahan, Robert H.
Diamond, Michael S.
Bloom, Jesse D.
Crowe, James E., Jr.
[J]. NATURE MICROBIOLOGY, 2021, 6 (10) : 1233 - +
[8] Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19
Dougan, M.
Nirula, A.
Azizad, M.
Mocherla, B.
Gottlieb, R. L.
Chen, P.
Hebert, C.
Perry, R.
Boscia, J.
Heller, B.
Morris, J.
Crystal, C.
Igbinadolor, A.
Huhn, G.
Cardona, J.
Shawa, I
Kumar, P.
Adams, A. C.
Van Naarden, J.
Custer, K. L.
Durante, M.
Oakley, G.
Schade, A. E.
Holzer, T. R.
Ebert, P. J.
Higgs, R. E.
Kallewaard, N. L.
Sabo, J.
Patel, D. R.
Dabora, M. C.
Klekotka, P.
Shen, L.
Skovronsky, D. M.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2021, 385 (15) : 1382 - 1392
[9] A proportional hazards model for the subdistribution of a competing risk
Fine, JP
Gray, RJ
[J]. JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION, 1999, 94 (446) : 496 - 509
[10] A CLASS OF K-SAMPLE TESTS FOR COMPARING THE CUMULATIVE INCIDENCE OF A COMPETING RISK
GRAY, RJ
[J]. ANNALS OF STATISTICS, 1988, 16 (03) : 1141 - 1154

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