Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

Ivan O. Rosas; Norbert Bräu; Michael Waters; Ronaldo C. Go; Atul Malhotra; Bradley D. Hunter; Sanjay Bhagani; Daniel Skiest; Sinisa Savic; Ivor S. Douglas; Julia Garcia-Diaz; Mariam S. Aziz; Nichola Cooper; Taryn Youngstein; Lorenzo Del Sorbo; David J.De La Zerda; Andrew Ustianowski; Antonio Cubillo Gracian; Kevin G. Blyth; Jordi Carratalà; Bruno François; Thomas Benfield; Derrick Haslem; Paolo Bonfanti; Cor H. van der Leest; Nidhi Rohatgi; Lothar Wiese; Charles Edouard Luyt; Rebecca N. Bauer; Fang Cai; Ivan T. Lee; Balpreet Matharu; Louis Metcalf; Steffen Wildum; Emily Graham; Larry Tsai; Min Bao

doi:10.1016/j.eclinm.2022.101409

Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

Ivan O. Rosas, Norbert Bräu, Michael Waters, Ronaldo C. Go, Atul Malhotra, Bradley D. Hunter, Sanjay Bhagani, Daniel Skiest, Sinisa Savic, Ivor S. Douglas, Julia Garcia-Diaz, Mariam S. Aziz, Nichola Cooper, Taryn Youngstein, Lorenzo Del Sorbo, David J.De La Zerda, Andrew Ustianowski, Antonio Cubillo Gracian, Kevin G. Blyth, Jordi CarratalàBruno François, Thomas Benfield, Derrick Haslem, Paolo Bonfanti, Cor H. van der Leest, Nidhi Rohatgi, Lothar Wiese, Charles Edouard Luyt, Rebecca N. Bauer, Fang Cai, Ivan T. Lee, Balpreet Matharu, Louis Metcalf, Steffen Wildum, Emily Graham, Larry Tsai, Min Bao

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference –0·5% [95% CI –9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase–quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti–SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

Original language	English
Article number	101409
Journal	eClinicalMedicine
Volume	47
DOIs	https://doi.org/10.1016/j.eclinm.2022.101409
State	Published - May 2022

Keywords

Coronavirus disease 2019
Interleukin-6
Randomised controlled trial
Severe acute respiratory syndrome coronavirus-2
Tocilizumab
Viral load

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Rosas, I. O., Bräu, N., Waters, M., Go, R. C., Malhotra, A., Hunter, B. D., Bhagani, S., Skiest, D., Savic, S., Douglas, I. S., Garcia-Diaz, J., Aziz, M. S., Cooper, N., Youngstein, T., Sorbo, L. D., Zerda, D. J. D. L., Ustianowski, A., Gracian, A. C., Blyth, K. G., ... Bao, M. (2022). Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA). eClinicalMedicine, 47, Article 101409. https://doi.org/10.1016/j.eclinm.2022.101409

@article{712db54ac96442d5a999c381867abe1a,

title = "Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)",

abstract = "Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference –0·5% [95% CI –9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase–quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti–SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.",

keywords = "Coronavirus disease 2019, Interleukin-6, Randomised controlled trial, Severe acute respiratory syndrome coronavirus-2, Tocilizumab, Viral load",

author = "Rosas, {Ivan O.} and Norbert Br{\"a}u and Michael Waters and Go, {Ronaldo C.} and Atul Malhotra and Hunter, {Bradley D.} and Sanjay Bhagani and Daniel Skiest and Sinisa Savic and Douglas, {Ivor S.} and Julia Garcia-Diaz and Aziz, {Mariam S.} and Nichola Cooper and Taryn Youngstein and Sorbo, {Lorenzo Del} and Zerda, {David J.De La} and Andrew Ustianowski and Gracian, {Antonio Cubillo} and Blyth, {Kevin G.} and Jordi Carratal{\`a} and Bruno Fran{\c c}ois and Thomas Benfield and Derrick Haslem and Paolo Bonfanti and {van der Leest}, {Cor H.} and Nidhi Rohatgi and Lothar Wiese and Luyt, {Charles Edouard} and Bauer, {Rebecca N.} and Fang Cai and Lee, {Ivan T.} and Balpreet Matharu and Louis Metcalf and Steffen Wildum and Emily Graham and Larry Tsai and Min Bao",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = may,

doi = "10.1016/j.eclinm.2022.101409",

language = "English",

volume = "47",

journal = "eClinicalMedicine",

issn = "2589-5370",

publisher = "Lancet Publishing Group",

}

Rosas, IO, Bräu, N, Waters, M, Go, RC, Malhotra, A, Hunter, BD, Bhagani, S, Skiest, D, Savic, S, Douglas, IS, Garcia-Diaz, J, Aziz, MS, Cooper, N, Youngstein, T, Sorbo, LD, Zerda, DJDL, Ustianowski, A, Gracian, AC, Blyth, KG, Carratalà, J, François, B, Benfield, T, Haslem, D, Bonfanti, P, van der Leest, CH, Rohatgi, N, Wiese, L, Luyt, CE, Bauer, RN, Cai, F, Lee, IT, Matharu, B, Metcalf, L, Wildum, S, Graham, E, Tsai, L & Bao, M 2022, 'Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)', eClinicalMedicine, vol. 47, 101409. https://doi.org/10.1016/j.eclinm.2022.101409

TY - JOUR

T1 - Tocilizumab in patients hospitalised with COVID-19 pneumonia

T2 - Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

AU - Rosas, Ivan O.

AU - Bräu, Norbert

AU - Waters, Michael

AU - Go, Ronaldo C.

AU - Malhotra, Atul

AU - Hunter, Bradley D.

AU - Bhagani, Sanjay

AU - Skiest, Daniel

AU - Savic, Sinisa

AU - Douglas, Ivor S.

AU - Garcia-Diaz, Julia

AU - Aziz, Mariam S.

AU - Cooper, Nichola

AU - Youngstein, Taryn

AU - Sorbo, Lorenzo Del

AU - Zerda, David J.De La

AU - Ustianowski, Andrew

AU - Gracian, Antonio Cubillo

AU - Blyth, Kevin G.

AU - Carratalà, Jordi

AU - François, Bruno

AU - Benfield, Thomas

AU - Haslem, Derrick

AU - Bonfanti, Paolo

AU - van der Leest, Cor H.

AU - Rohatgi, Nidhi

AU - Wiese, Lothar

AU - Luyt, Charles Edouard

AU - Bauer, Rebecca N.

AU - Cai, Fang

AU - Lee, Ivan T.

AU - Matharu, Balpreet

AU - Metcalf, Louis

AU - Wildum, Steffen

AU - Graham, Emily

AU - Tsai, Larry

AU - Bao, Min

PY - 2022/5

Y1 - 2022/5

N2 - Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference –0·5% [95% CI –9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase–quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti–SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

AB - Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference –0·5% [95% CI –9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase–quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti–SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

KW - Coronavirus disease 2019

KW - Interleukin-6

KW - Randomised controlled trial

KW - Severe acute respiratory syndrome coronavirus-2

KW - Tocilizumab

KW - Viral load

UR - http://www.scopus.com/inward/record.url?scp=85136251056&partnerID=8YFLogxK

U2 - 10.1016/j.eclinm.2022.101409

DO - 10.1016/j.eclinm.2022.101409

M3 - Article

AN - SCOPUS:85136251056

SN - 2589-5370

VL - 47

JO - eClinicalMedicine

JF - eClinicalMedicine

M1 - 101409

ER -

Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

Abstract

Keywords

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