Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia

Rosas, Iván O.; Bräu, Norbert; Waters, Michael R.; Go, Ronaldo C.; Hunter, Bradley; Bhagani, Sanjay; Skiest, Daniel J.; Aziz, Mariam; Cooper, Nichola; Douglas, Ivor S.; Savic, Sinisa; Youngstein, Taryn; Sorbo, Lorenzo Del; Gracián, Antonio Cubillo; Zerda, David J. De La; Ustianowski, Andrew; Bao, Min; Dimonaco, Sophie; Graham, Emily; Matharu, Balpreet; Spotswood, Helen; Tsai, Larry; Malhotra, Atul

doi:10.1101/2020.08.27.20183442

Cited by 134 publications

(197 citation statements)

References 21 publications

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“…39 Besides EMPACTA, the efficacy of tocilizumab in Covid-19 has been examined in one other randomized placebo-controlled trial, COVACTA. 35 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

“…[30][31][32][33][34] Although the randomized, placebo-controlled COVACTA trial-which enrolled patients with a range of disease severity, including 38% of patients receiving mechanical ventilation-did not meet its primary endpoint, its results suggested that tocilizumab may have a positive effect on recovery time and need for intensive care, which warrants further investigation. 35 The global phase III EMPACTA (Evaluating Minority Patients with Actemra) clinical trial investigated the safety and efficacy of tocilizumab in hospitalized, nonventilated patients with Covid-19 pneumonia, with an emphasis on enrolling high-risk and racial and ethnic minority populations.…”

Section: Introductionmentioning

confidence: 99%

“…Corticosteroid and antiviral use was generally balanced between arms, and EMPACTA demonstrated the added clinical benefit of tocilizumab. In COVACTA, the median time to hospital discharge was 20 and 28 days in the tocilizumab and placebo arms, respectively, whereas in EMPACTA, it was 6 and 7.5 days, respectively 35. This may reflect patients who were more severely ill or different comorbid conditions at study baseline inCOVACTA, as well as improvements in the standards of care and different proportions of patients receiving concomitant steroids and antivirals.…”

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confidence: 98%

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Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia

Salama

Han²,

Yau³

et al. 2020

Preprint

127

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Background: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab was evaluated in patients hospitalized with Covid-19 pneumonia. Methods: Nonventilated patients hospitalized with Covid-19 pneumonia were randomized (2:1) to tocilizumab (8 mg/kg intravenous) or placebo plus standard care. Sites enrolling high-risk and minority populations were emphasized. The primary endpoint was cumulative proportion of patients requiring mechanical ventilation or who had died by Day 28. Results: Of 389 randomized patients, 249 patients received tocilizumab and 128 received placebo in the modified intent-to-treat population (Hispanic/Latino, 56.0%; Black/African American, 14.9%; American Indian/Alaska Native, 12.7%; White, 12.7%; other/unknown, 3.7%). The cumulative proportion (95% confidence interval [CI]) of patients requiring mechanical ventilation or who had died by Day 28 was 12.0% (8.52% to 16.86%) and 19.3 % (13.34% to 27.36%) for the tocilizumab and placebo arms, respectively (log-rank P=0.0360; hazard ratio, 0.56 [95% CI, 0.33 to 0.97]). Median time to clinical failure up to Day 28 favored tocilizumab over placebo (hazard ratio 0.55 [95% CI, 0.33 to 0.93]). All-cause mortality by Day 28 was 10.4% with tocilizumab and 8.6% with placebo (weighted difference, 2.0% [95% CI, -5.2% to 7.8%). In the safety population, serious adverse events occurred in 15.2% of tocilizumab patients (38/250 patients) and 19.7% of placebo patients (25/127). Conclusions: This trial demonstrated the efficacy and safety of tocilizumab over placebo in reducing the likelihood of progression to requiring mechanical ventilation or death in nonventilated patients hospitalized with Covid-19 pneumonia.

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Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia

Salama

Han²,

Yau³

et al. 2020

Preprint

127

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“…RCT: No significant benefit 6. WHO temporarily paused trial for HCQ over safety concern but later resumed on June 03, 2020 7. US FDA emergency use approval revoked on June 15, 2020 HCQ and AZITHROMYCIN` K [ 53 , 67 , 84 – 94 ] 10 TOCILIZUMAB [ 95 , 96 , 98 – 100 , 106 ] Rheumatoid arthritis, and other inflammatory and autoimmune disorder IL-6 receptor antagonist 1. Retrospective study: Improve clinical presentations without significant side effects 2.…”

Section: Repurposed Therapeuticsmentioning

confidence: 99%

SARS-CoV-2 therapeutics: how far do we stand from a remedy?

Singh

Gupta

2021

Pharmacol. Rep

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“…Random-effects meta-analysis showed no evidence of a difference between tocilizumab and control interventions on serious adverse events (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I 2 = 77.4%; five trials; very low certainty) ( S55 Fig, S13 Table). either unclear [90,114], 28 days [111,113], or 30 days [112] after randomization. The trial sequential analysis showed that we did not have enough information to confirm or reject that tocilizumab versus control reduces the risk of serious adverse events with a relative risk reduction of 20%.…”

Section: Meta-analysis Of All-cause Mortalitymentioning

confidence: 99%

Interventions for treatment of COVID-19: second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Juul

Feinberg

Siddiqui

et al. 2020

Preprint

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BackgroundCOVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19.Methods and findingsWe planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology.We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias.Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached.Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events.Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects.Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects.Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexidine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects.Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%.Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%.All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses.ConclusionsNo evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intraveneous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexidine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19.Systematic review registration PROSPERO CRD42020178787Author summaryWhy was this study done?Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly worldwide, causing an international outbreak of the corona virus disease 2019 (COVID-19).There is a need for a living systematic review evaluating the beneficial and harmful effects of all possible interventions for treatment of COVID-19.What did the researchers do and find?We conducted the second edition of our living systematic review with meta-analyses and Trial sequential analyses to compare the effects of all treatment interventions for COVID-19.Very low certainty evidence indicated that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intraveneous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexidine might reduce the risk of non-serious adverse events.Nine single trials showed statistically significant results on our predefined outcomes but were underpowered to confirm or reject realistic intervention effects.None of the remaining trials showed evidence of a difference of the experimental interventions on our predefined outcomes.What do these findings mean?No evidence-based treatment for COVID-19 currently existsMore high quality, low risk of bias randomized clinical trials are urgently needed.

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Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia

Cited by 134 publications

References 21 publications

Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia

Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia

SARS-CoV-2 therapeutics: how far do we stand from a remedy?

Interventions for treatment of COVID-19: second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

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