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Meta-Analysis
. 2023 Jun 1;6(6):CD013881.
doi: 10.1002/14651858.CD013881.pub2.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review

Lina Ghosn  1   2   3 , Rouba Assi  1   2   3 , Theodoros Evrenoglou  3 , Brian S Buckley  4 , Nicholas Henschke  4 , Katrin Probyn  4 , Carolina Riveros  2   3 , Mauricia Davidson  3 , Carolina Graña  1   2   3 , Hillary Bonnet  1   3 , Alexander Jarde  3 , Camila Ávila  5 , Camilla Hansen Nejstgaard  6   7 , Sonia Menon  1 , Gabriel Ferrand  1 , Philipp Kapp  8 , Claudia Breuer  8   9 , Christine Schmucker  8   9 , Yanina Sguassero  4 , Thu Van Nguyen  1 , Declan Devane  10   11   12 , Joerg J Meerpohl  8   9 , Gabriel Rada  5   13 , Asbjørn Hróbjartsson  6   7 , Giacomo Grasselli  14 , David Tovey  1 , Philippe Ravaud  1   2   3 , Anna Chaimani  1   2   3 , Isabelle Boutron  1   2   3
Affiliations
Meta-Analysis

Interleukin-6 blocking agents for treating COVID-19: a living systematic review

Lina Ghosn et al. Cochrane Database Syst Rev. .

Abstract

Background: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19.

Objectives: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19.

Search methods: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022.

Selection criteria: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity.

Data collection and analysis: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes.

Main results: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022. The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies. Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence). The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain.

Authors' conclusions: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

PubMed Disclaimer

Conflict of interest statement

Lina Ghosn: none known.

Rouba Assi: none known.

Theodoros Evrenoglou: none known.

Brian Buckley: no relevant interests; employed as a systematic reviewer by Cochrane Response during the conduct of the review (with funding from the World Health Organization).

Nicholas Henschke: none known.

Katrin Probyn: none known.

Carolina Riveros: no relevant interests; works as a health professional (epidemiologist).

Mauricia Davidson: none known.

Carolina Graña: none known.

Hillary Bonnet: none known.

Alexander Jarde: none known.

Camila Ávila: none known.

Camilla Hansen Nejstgaard: none known.

Sonia Menon: P95 (consultant).

Gabriel Ferrand: none known.

Philipp Kapp: none known.

Christine Scmucker: none known.

Claudia Breuer: none known

Yanina Sguassero: Cochrane Response (employment); editor of Cochrane Clinical Answers.

Thu Van Nguyen: none known.

Declan Devane: Health Research Board (grant/contract); Registered Midwife but no longer in clinical practice; Editor of Cochrane Pregnancy and Childbirth.

Joerg Meerpohl: none known.

Gabriel Rada: none known.

Asbjørn Hróbjartsson: no relevant interests; Editor of Cochrane Methodology.

Giacomo Grasselli: Pfizer (speaker arrangement).

David Tovey: no relevant interests; Emeritus Editor in Chief and Feedback Editors for two Cochrane Review Groups.

Philippe Ravaud: no relevant interests; involved in Mariette CORIMUNO‐19 Collaborative 2021 (The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP‐HP Foundation).

Anna Chaimani: none known.

Isabelle Boutron: no relevant interests; member of Cochrane Editorial Board.

Figures

1
1
Flowchart of included randomized controlled trials (RCTs) of interleukin 6 (IL‐6) blocking agents (last search date: 7 June 2022) ICTRP: World Health Organization (WHO) International Clinical Trials Registry Platform a Multiple arm RCTs evaluated both tocilizumab and sarilumab (one published and one unpublished result), b One factorial RCT evaluated tocilizumab and siltuximab, and consequently, they appear twice.
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Funnel plot Tocilizumab vs standard care or placebo. All cause mortality D28
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8.1.2 Funnel plot Tocilizumab compared to standard care or placebo
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8.1.2 Funnel plot Tocilizumab compared to standard care or placebo. Clinical improvement D28
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8.1.2 Funnel plot Tocilizumab compared to standard care or placebo. WHO score 7 D28
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8.1.2 Funnel plot Tocilizumab compared to standard care or placebo. Adverse events
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8.1.2 Funnel plot Tocilizumab compared to standard care or placebo. Serious adverse events
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Analysis 1.1.1 Tocilizumab versus placebo or standard care. Outcome: Clinical improvement 28
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Analysis 1.1.2 Tocilizumab versus placebo or standard care. Outcome: Clinical improvement D60
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Analysis 1.1.3 Tocilizumab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
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Analysis 1.1.4 Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Analysis 1.1.5 Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Analysis 1.1.6 Tocilizumab versus placebo or standard care. Outcome: Adverse events
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Analysis 1.1.7 Tocilizumab versus placebo or standard care. Outcome: Serious adverse events
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Analysis 1.2.1 Tocilizumab versus placebo or standard care. Outcome: Time to clinical improvement
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Analysis 1.2.2 Tocilizumab versus placebo or standard care. Outcome: Time to WHO progression score (level 7 and above)
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Analysis 1.2.3 Tocilizumab versus placebo or standard care. Outcome: Time to death
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Analysis 2.1.1 Sarilumab versus placebo or standard care. Outcome: Clinical improvement D28 Sivapalasingam 2022: Sivapalasingam 2022.1 refers to the phase 2 results; Sivapalasingam 2022.2 refers to the phase 3 results.
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Analysis 2.1.2 Sarilumab versus placebo or standard care. Outcome: Clinical improvement D60
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Analysis 2.1.3 Sarilumab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
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Analysis 2.1.4 Sarilumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Analysis 2.1.5 Sarilumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Analysis 2.1.6 Sarilumab versus placebo or standard care. Outcome: Adverse events
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Analysis 2.1.7 Sarilumab versus placebo or standard care. Outcome: Serious adverse events
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Analysis 2.2.1 Sarilumab versus placebo or standard care. Outcome: Time to clinical improvement
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Analysis 2.2.2 Sarilumab versus placebo or standard care. Time to WHO Clinical Progression Score of level 7 or above
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Analysis 2.2.3 Sarilumab versus placebo or standard care. Outcome: Time to death
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Analysis 3.1.1 Clazakizumab versus placebo or standard care. Outcome: Clinical improvement 28
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Analysis 3.1.2 Clazakizumab versus placebo or standard care. Outcome: Clinical improvement D60
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Analysis 3.1.3 Clazakizumab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
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Analysis 3.1.4 Clazakizumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Analysis 3.1.5 Clazakizumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Analysis 3.1.6 Clazakizumab versus placebo or standard care. Outcome: Adverse events
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Analysis 3.1.7 Clazakizumab versus placebo or standard care. Outcome: Serious adverse events
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Analysis 4.1.1 Olokizumab versus placebo or standard care. Outcome: Clinical improvement 28
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Analysis 4.1.2 Olokizumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Analysis 4.1.3 Olokizumab versus placebo or standard care. Outcome: Serious adverse events
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Analysis 5.1.1 Siltuximab versus placebo or standard care. Outcome: Clinical improvement 28
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Analysis 5.1.2 Siltuximab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
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Analysis 5.1.3 Siltuximab versus placebo or standard care. Outcome: All‐cause mortality D28
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Analysis 5.1.4 Siltuximab versus placebo or standard care. Outcome: All‐cause mortality D60
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Analysis 5.1.5 Siltuximab versus placebo or standard care. Outcome: Serious adverse events
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Analysis 5.2.1 Siltuximab versus placebo or standard care. Outcome: Time to death
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Analysis 6.1.1 Levilimab versus placebo or standard care. Outcome: Clinical improvement 28
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Analysis 6.1.2 Levilimab versus placebo or standard care. Outcome: All‐cause mortality D28
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Analysis 6.1.3 Levilimab versus placebo or standard care. Outcome: All‐cause mortality D60
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Analysis 6.1.4 Levilimab versus placebo or standard care. Outcome: Adverse events
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Analysis 6.1.5 Levilimab versus placebo or standard care. Outcome: Serious adverse events
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Subgroup analysis. 1.3.1 Funding. Tocilizumab versus placebo or standard care. Outcome: Clinical improvement D28
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Subgroup analysis.1.3.2 Funding. Tocilizumab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
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Subgroup analysis.1.3.3 Funding. Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Subgroup analysis. 1.3.4 Funding. Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Subgroup analysis. 1.3.5 Funding. Tocilizumab versus placebo or standard care. Outcome: Adverse events
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Subgroup analysis. 1.3.6 Funding. Tocilizumab versus placebo or standard care. Outcome: Serious adverse events
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Subgroup analysis. 1.4.1 Location. Tocilizumab versus placebo or standard care. Outcome: Clinical improvement D28
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Subgroup analysis. 1.4.2 Location. Tocilizumab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
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Subgroup analysis.1.4.3 Location. Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Subgroup analysis. 1.4.4 Location. Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Subgroup analysis. 1.4.5 Location. Tocilizumab versus placebo or standard care. Outcome: Adverse events
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Subgroup analysis. 1.4.6 Location. Tocilizumab versus placebo or standard care. Outcome: Serious adverse events
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Subgroup analysis. 1.5.1 Conflict of Interests. Tocilizumab versus placebo or standard care. Outcome: Clinical improvement D28
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Subgroup analysis. 1.5.2 Conflict of Interests. Tocilizumab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
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Subgroup analysis. 1.5.3 Conflict of Interests. Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Subgroup analysis. 1.5.4 Conflict of Interests. Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Subgroup analysis. 1.5.5 Conflict of Interests. Tocilizumab versus placebo or standard care. Outcome: Adverse events
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Subgroup analysis. 1.5.6 Conflict of Interests. Tocilizumab versus placebo or standard care. Outcome: Serious adverse events
67
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Subgroup analysis. 1.6.1 Severity. Tocilizumab versus placebo or standard care. Outcome: Clinical improvement D28
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Subgroup analysis. 1.6.2 Severity. Tocilizumab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
69
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Subgroup analysis. 1.6.3 Severity. Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Subgroup analysis. 1.6.4 Severity. Tocilizumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Subgroup analysis. 1.6.5 Severity. Tocilizumab versus placebo or standard care. Outcome: Serious adverse events
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Subgroup analysis. 2.3.1 Funding. Sarilumab versus placebo or standard care. Outcome: Clinical improvement D28
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Subgroup analysis.2.3.3 Funding. Sarilumab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
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Subgroup analysis.2.3.4 Funding. Sarilumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Subgroup analysis. 2.3.5 Funding. Sarilumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Subgroup analysis. 2.3.6 Funding. Sarilumab versus placebo or standard care. Outcome: Adverse events
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Subgroup analysis. 2.3.7 Funding. Sarilumab versus placebo or standard care. Outcome: Serious adverse events
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Subgroup analysis.2.4.1 Location. Sarilumab versus placebo or standard care. Outcome: All‐cause mortality D28
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Subgroup analysis. 2.4.2 Location. Sarilumab versus placebo or standard care. Outcome: All‐cause mortality D60
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80
Subgroup analysis. 2.4.3 Location. Sarilumab versus placebo or standard care. Outcome: Adverse events
81
81
Subgroup analysis. 2.4.4 Location. Sarilumab versus placebo or standard care. Outcome: Serious adverse events
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82
Subgroup analysis. 2.5.1 Conflict of Interests. Sarilumab versus placebo or standard care. Outcome: Clinical improvement D28
83
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Subgroup analysis. 2.5.2 Conflict of Interests. Sarilumab versus placebo or standard care. Outcome: WHO progression score (level 7 or above) D28
84
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Subgroup analysis. 2.5.3 Conflict of Interests. Sarilumab versus placebo or standard care. Outcome: All‐cause mortality D28
85
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Subgroup analysis. 2.5.4 Conflict of Interests. Sarilumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Subgroup analysis. 2.5.5 Conflict of Interests. Sarilumab versus placebo or standard care. Outcome: Adverse events
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Subgroup analysis. 2.5.6 Conflict of Interests. Sarilumab versus placebo or standard care. Outcome: Serious adverse events
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Subgroup analysis. 3.3.1 Conflict of interest. Clazakizumab versus placebo. Outcome: All‐cause mortality D28
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Subgroup analysis. 3.3.2 Conflict of interest. Clazakizumab versus placebo or standard care. Outcome: All‐cause mortality D60
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Subgroup analysis. 3.3.3 Conflict of interest. Clazakizumab versus placebo or standard care. Outcome: Serious adverse events
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References

References to studies included in this review

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    1. ISRCTN50189673. A randomised trial of treatments to prevent death in patients hospitalised with COVID-19 (coronavirus). isrctn.com/ISRCTN50189673 (first received 30 March 2020).
    1. NCT04381936. Randomised evaluation of COVID-19 therapy (RECOVERY). clinicaltrials.gov/ct2/show/NCT04381936 (first received 11 May 2020).
    1. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 2021;397(10285):1637-45. [DOI: 10.1016/S0140-6736(21)00676-0] - DOI - PMC - PubMed
IMMCOVA 2021 {unpublished data only}
    1. EudraCT 2020-001748-24. A multi-center, randomized, open-label study in patients with COVID-19 and respiratory distress not requiring mechanical ventilation, to compare standard-of-care with anakinra and tocilizumab treatment.The Immunomodulation-CoV Assessment (ImmCoVA) study. www.clinicaltrialsregister.eu/ctr-search/trial/2020-001748-24/SE (first received 20 April 2020).
    1. NCT04412291. A study in patients with COVID-19 and respiratory distress not requiring mechanical ventilation, to compare standard-of-care with Anakinra and Tocilizumab treatment the immunomodulation-CoV assessment (ImmCoVA) Study. clinicaltrials.gov/ct2/show/NCT04412291 (first received 2 June 2020).
    1. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, Spiga F, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA 2021;326(6):499-518. [DOI: 10.1001/jama.2021.11330] [PMID: ] - DOI - PMC - PubMed
Jordan 2021 {unpublished data only}
    1. Jordan S. Clazakizumab (Anti-Interleukin 6 (IL-6) Monoclonal) compared to placebo for coronavirus disease 2019 (COVID-19) NCT04348500. clinicaltrials.gov/ct2/show/NCT04348500 2021.
Lescure 2021 {published data only (unpublished sought but not used)}
    1. Lescure FX, Honda H, Fowler RA, Lazar JS, Shi G, Wung P, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Respiratory Medicine 2021;9(5):522-532. - PMC - PubMed
    1. Lescure FX, Honda H, Fowler RA, Lazar JS, Shi G, Wung P, et al. Sarilumab treatment of hospitalised patients with severe or critical COVID-19: a multinational, randomised, adaptive, phase 3, double-blind, placebo-controlled trial. medRxiv [Preprint] 2021. [DOI: 10.1101/2021.02.01.21250769] - DOI
    1. NCT04327388. Sarilumab COVID-19. clinicaltrials.gov/ct2/show/NCT04327388 (first received 31 March 2020).
Lomakin 2021 {published data only (unpublished sought but not used)}
    1. Lomakin NV, Bakirov BA, Protsenko DN, Mazurov VI, Musaev GH, Moiseeva OM, et al. The efficacy and safety of levilimab in severely ill COVID-19 patients not requiring mechanical ventilation: results of a multicenter randomized double-blind placebo-controlled phase III CORONA clinical study. Inflammation Research 2021;70(10-12):1233-1246. - PMC - PubMed
    1. NCT04397562. A clinical trial of the efficacy and safety of levilimab (BCD-089) in patients with severe COVID-19 [A multicenter, randomized, double-blind, placebo-controlled, adaptively designed clinical trial of the efficacy and safety of levilimab (BCD-089) in patients with severe COVID-19]. clinicaltrials.gov/ct2/show/NCT04397562 (first received 21 May 2020).
Lonze 2022 {published data only (unpublished sought but not used)}
    1. Lonze BE, Spiegler P, Wesson RN, Alachkar N, Petkova E, Weldon EP, et al. A randomized double-blinded placebo controlled trial of Clazakizumab for the treatment of COVID-19 pneumonia with hyperinflammation. Critical Care Medicine 2022;50(9):1348-59. [DOI: 10.1097/CCM.0000000000005591] - DOI - PMC - PubMed
    1. NCT04343989. A randomized placebo-controlled safety and dose-finding study for the use of the IL-6 inhibitor clazakizumab in patients with life-threatening COVID-19 Infection. clinicaltrials.gov/ct2/show/ (first received 14 April 2020).
    1. NCT04659772. A study to evaluate clazakizumab in patients with life-threatening COVID-19 infection. clinicaltrials.gov/ct2/show/NCT04659772 (first received 9 December 2020).
Mariette 2021 {published and unpublished data}
    1. Mariette X. Sarilumab in adults hospitalised with moderate-to-severe COVID-19 pneumonia (CORIMUNO-SARI-1): An open-label randomised controlled trial. The Lancet Rheumatology 2022;4(1):e24-e32. - PMC - PubMed
Merchante 2021 {published data only (unpublished sought but not used)}
    1. Merchante N, Cárcel S, Garrido-Gracia JC, Trigo-Rodríguez M, Moreno MÁ E, León-López R, et al. Early use of Sarilumab in patients hospitalized with COVID-19 pneumonia and features of systemic inflammation: the SARICOR randomized clinical trial. Antimicrobial Agents and Chemotherapy 2022;66(2):e0210721. - PMC - PubMed
    1. NCT04357860. Clinical trial of sarilumab in adults with COVID-19. clinicaltrials.gov/ct2/show/NCT04357860 (first received 22 April 2020).
Rosas 2022 {published and unpublished data}
    1. NCT04320615. A study to evaluate the safety and efficacy of tocilizumab in patients with severe COVID-19 pneumonia (COVACTA) [A randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of tocilizumab in patients with severe COVID-19 pneumonia]. clinicaltrials.gov/ct2/show/NCT04320615 (first received 25 March 2020).
    1. Rosas IO, Brau N, Waters M, Go RC, Malhotra A, Hunter BD, et al. Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA). EClinicalMedicine 2022;47:101409. - PMC - PubMed
    1. Rosas IO, Bräu N, Waters M, Go R, Hunter BD, Bhagani S, et al. Tocilizumab in hospitalized patients with COVID-19 pneumonia. medRxiv [Preprint] 2020. [DOI: 10.1101/2020.08.27.20183442] - DOI - PMC - PubMed
    1. Rosas IO, Bräu N, Waters M, Go R, Hunter BD, Bhagani S, et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. New England Journal of Medicine 2021;Feb 25:Epub ahead of print. [DOI: 10.1056/NEJMoa2028700] [PMID: ] - DOI - PMC - PubMed
Rutgers 2021 {published data only}
    1. NL8504. Pre-emptive tocilizumab in hypoxic COVID-19 patients, a prospective randomized trial. trialregister.nl/trial/8504 (first received 6 April 2020).
    1. Rutgers A, Westerweel PE, Holt B, Postma S, Vonderen MGA, Piersma DP, et al. Timely administration of tocilizumab improves survival of hospitalized COVID-19 patients. SSRN 2021 [Preprint]. [DOI: 10.2139/ssrn.3834311] - DOI - PMC - PubMed
Salama 2020 {published and unpublished data}
    1. NCT04372186. A study to evaluate the efficacy and safety of tocilizumab in hospitalized participants with COVID-19 pneumonia (EMPACTA). clinicaltrials.gov/ct2/show/NCT04372186 (first received May 1 2020).
    1. Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. New England Journal of Medicine 2021;1(384):20-30. [DOI: 10.1056/NEJMoa2030340] [PMID: ] - DOI - PMC - PubMed
Salvarani 2020 {published data only (unpublished sought but not used)}
    1. NCT04346355. Efficacy of early administration of tocilizumab in COVID-19 patients. clinicaltrials.gov/ct2/show/NCT04346355 (first received 15 April 2020).
    1. Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, et al, RCT-TCZ-COVID-19 Study Group. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia. A randomized clinical trial. JAMA Internal Medicine 2021;181(1):24-31. [DOI: 10.1001/jamainternmed.2020.6615] [PMID: ] - DOI - PMC - PubMed
Samsonov 2022 {unpublished data only}
    1. Samsonov M. Study of the efficacy and safety of a single administration of Olokizumab and RPH-104 with standard therapy in patients with severe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection (COVID-19). clinicaltrials.gov/ct2/show/NCT04380519 (first received 24 January 2022).
Sancho‐Lopez 2021 {published data only (unpublished sought but not used)}
    1. Sancho-López A, Caballero-Bermejo AF, Ruiz-Antorán B, Múñez Rubio E, García Gasalla M, Buades J, et al. Efficacy and safety of Sarilumab in patients with COVID19 pneumonia: A randomized, phase III clinical trial (SARTRE Study). Infectious Diseases and Therapy 2021;10(4):2735-2748. - PMC - PubMed
Sivapalasingam 2022 {published data only (unpublished sought but not used)}
    1. NCT04315298. Evaluation of the efficacy and safety of sarilumab in hospitalized patients with COVID-19 [An adaptive phase 2/3, randomized, double-blind, placebo-controlled study assessing efficacy and safety of sarilumab for hospitalized patients with COVID-19]. clinicaltrials.gov/ct2/show/ (first received 19 March 2020).
    1. Sivapalasingam S, Lederer DJ, Bhore R, Hajizadeh N, Criner G, Hosain R, et al. Efficacy and safety of Sarilumab in hospitalized patients with COVID-19: A randomized clinical trial. Clinical Infectious Diseases 2022;75(1):e380-8. [DOI: 10.1093/cid/ciac153] - DOI - PMC - PubMed
Soin 2021 {published data only (unpublished sought but not used)}
    1. CTRI/2020/05/025369. A study on treatment of COVID-19 patients with study drug along with standard of care. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2020/05/025369 (first received 27 May 2020).
    1. Soin AS, Kumar K, Choudhary NS, Sharma P, Mehta Y, Kataria S, et al. Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet Respiratory Medicine 2021;9(5):511-21. - PMC - PubMed
Stone 2020 {published data only (unpublished sought but not used)}
    1. NCT04356937. Efficacy of tocilizumab on patients with COVID-19. clinicaltrials.gov/ct2/show/NCT04356937 (first received 22 April 2020).
    1. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, et al, BACC Bay Tocilizumab Trial Investigators. Efficacy of tocilizumab in patients hospitalized with Covid-19. New England Journal of Medicine 2020;383(24):2333-44. [DOI: 10.1056/NEJMoa2028836] [PMID: ] - DOI - PMC - PubMed
Talaschian 2021 {published data only (unpublished sought but not used)}
    1. IRCT20081027001411N4. Effect of TOCILIZUMAB (ACTEMRA) on treatment of COVID-19 [Study of tocilizumab effect on treatment and clinical symptoms and laboratory signs of Iranian COVID-19 patients: a ‎clinical trial study].. en.irct.ir/trial/48396 (first received 9 July 2020).
    1. Talaschian M, Akhtari M, Mahmoudi M, Mostafaei S, Jafary M, Sadat Husseini S et al. Tocilizumab failed to reduce mortality in severe COVID-19 Patients: Results from a ‎randomized controlled clinical trial. Research Square 2021 [Preprint]. [DOI: 10.21203/rs.3.rs-463921/v1] - DOI - PubMed
Veiga 2021 {published data only (unpublished sought but not used)}
    1. NCT04403685. Safety and efficacy of tocilizumab in moderate to severe COVID-19 with inflammatory markers (TOCIBRAS). clinicaltrials.gov/ct2/show/NCT04403685 (first received 27 May 2020).
    1. Veiga VC, Prats JA, Farias DL, Rosa RG, Dourado LK, Zampieri FG, et al, Coalition covid-19 Brazil VI Investigators. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ 2021;372:n84. [DOI: 10.1136/bmj.n84] [PMID: ] - DOI - PMC - PubMed
Wang 2021 {published data only (unpublished sought but not used)}
    1. ChiCTR2000029765. A multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19). chictr.org.cn/showprojen.aspx?proj=49409 (first received 13 February 2020).
    1. Wang D, Fu B, Peng Z, Yang D, Han M, Li M, et al. Tocilizumab ameliorates the hypoxia in COVID-19 moderate patients with bilateral pulmonary lesions: a randomized, controlled, open-label, multicenter trial. Available at SSRN: papers.ssrn.com/sol3/papers.cfm?abstract_id=3667681 [Preprint with The Lancet] 2020. [DOI: 10.2139/ssrn.3667681] - DOI
    1. Wang D, Fu B, Peng Z, Yang D, Han M, Li M, et al. Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial. Frontiers in Medicine 2021;15(3):486-494. - PMC - PubMed

References to studies excluded from this review

Albuquerque 2021 {published data only}
    1. Albuquerque AM, Tramujas L, Sewanan LR, Brophy JM. Tocilizumab in COVID-19 – A Bayesian reanalysis of RECOVERY. medRxiv 2021 [Preprint]. [DOI: 10.1101/2021.06.15.21258966] - DOI - PMC - PubMed
Rossotti 2020 {published data only}
    1. Rossotti R, Travi G, Ughi N, Corradin M, Baiguera C, Fumagalli R, et al. Safety and efficacy of anti-il6-receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis. Journal of Infection 2020;81(4):e11-7. - PMC - PubMed
Smieszek 2021 {published data only}
    1. Smieszek SP, Przychodzen BP, Polymeropoulos VM, Polymeropoulos CM, Polymeropoulos MH. Assessing the potential correlation of polymorphisms in the IL6R with relative IL6 elevation in severely ill COVID-19 patients'. Cytokine 2021;148:155662. - PMC - PubMed
Tom 2022 {published data only}
    1. Tom J, Bao M, Tsai L, Qamra A, Summers D, Carrasco-Triguero M, et al. Prognostic and predictive biomarkers in patients With Coronavirus Disease 2019 treated with tocilizumab in a randomized controlled trial. Critical Care Medicine 2022;50(3):398-409. - PMC - PubMed
Zafar 2021 {published data only}
    1. Zafar A, Khambhati J, Drobni Z, Gongora C, Horick NK, Foulkes A, et al. Effect of tocilizumab on cardiac injury and dysfunction in COVID-19. Journal of the American College of Cardiology 2021;77(18):3028. [DOI: 10.1016/S0735-1097(21)04383-7] - DOI

References to studies awaiting assessment

EUCTR2020‐001275‐32‐DK {unpublished data only}
    1. EUCTR2020-001275-32-DK. Effectiveness of Interleukin-6 receptor inhibitors in the management of patients with severe SARS-CoV-2 pneumonia: An open-Label multicenter sequential randomized controlled trial. clinicaltrialsregister.eu/ctr-search/trial/2020-001275-32/DK (first entered 2020-03-24).
EUCTR2020‐001290‐74‐ES {unpublished data only}
    1. EUCTR2020-001290-74-ES [Efficacy and safety of sarilumab in the early treatment of hospitalized patients with mild-moderate pneumonia and COVID19 infection versus standard of care]. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:202... (first received 11 April 2020).
EUCTR2020‐001408‐41‐DE {unpublished data only}
    1. EUCTR2020-001408-41-DE. A prospective, randomized, double blinded placebo-controlled trial to evaluate the efficacy and safety of tocilizumab in patients with severe COVID-19 pneumonia. clinicaltrialsregister.eu//ctr-search/trial/2020-001408-41/DE (first entered 2020-04-07).
EUCTR2020‐001770‐30‐BE {unpublished data only}
    1. EUCTR2020-001770-30-BE. COVID 19: Experimental use of tocilizumab (Roactemra®) in severe SARS-CoV-2 related pneumonia.. clinicaltrialsregister.eu//ctr-search/trial/2020-001770-30/BE (first entered 2020-04-15).
NCT04335071 {unpublished data only}
    1. NCT04335071. Tocilizumab in the treatment of Coronavirus induced disease (COVID-19) (CORON-ACT). clinicaltrials.gov/ct2/show/NCT04335071 (first received April 2, 2020).
NCT04381052 {unpublished data only}
    1. NCT04381052. Study for the use of the IL-6 Inhibitor clazakizumab in patients with life-threatening COVID-19 infection. clinicaltrials.gov/ct2/show/NCT04381052 (first received 8 May 2020).
NCT04616586 {unpublished data only}
    1. NCT04616586. Siltuximab in viral ARds. Study (SILVAR). clinicaltrials.gov/ct2/show/NCT04616586 (first received October 29, 2020).
NCT04690920 {unpublished data only}
    1. NCT04690920. Theranostic implication of complementary medicines against interleukin receptors and Gp-130 proteins. clinicaltrials.gov/ct2/show/NCT04690920 (first received 31 December 2020).

References to ongoing studies

ACTRN12620000580976 {unpublished data only}
    1. ACTRN12620000580976. Tocilizumab for the treatment of COVID-19 in intensive care patients: effect on days free of ventilatory support. anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379640&isReview... (first received 19 May 2020).
CTRI/2020/12/029793 {unpublished data only}
    1. CTRI/2020/12/029793. Efficacy and safety of tocilizumab in patients with severe COVID-19 pneumonia on steroid therapy: A prospective, randomized, double blind placebo-controlled trial. ctri.nic.in/Clinicaltrials/showallp.php?mid1=50303&EncHid=&userN... (first received 15 December 2020).
EUCTR2020‐001390‐76‐IT {unpublished data only}
    1. EUCTR2020-001390-76-IT. A phase 3, randomized, open-labeled, multi-center study comparing clinical efficacy and safety of intravenous sarilumab plus standard of care compared to standard of care, in the treatment of patients with severe COVID-19 pneumonia. clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-00... (first received 27 April 2020).
EUCTR2020‐001767‐86‐IE {published data only}
    1. EUCTR2020-001767-86-IE. An open-label, multi-centre, randomised trial comparing different doses of single-dose tocilizumab in adults with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive. clinicaltrialsregister.eu/ctr-search/trial/2020-001767-86/IE (first received 15 April 2020).
IRCT20200510047383N1 {unpublished data only}
    1. IRCT20200510047383N1. Evaluation of the effect of Tocilizumab on outcomes of the severe COVID-19 patients. www.irct.ir/trial/48024 (first received 15 May 2020).
IRCT20200525047570N1 {published data only}
    1. IRCT20200525047570N1. A comparative study of the effects of tocilizumab, interferon-gamma and vitamin C on the recovery of critically ill Covid-19 patients and cytokine storm. www.irct.ir/trial/48583 (first received 30 July 2020).
IRCT20201024049134N2 {unpublished data only}
    1. IRCT20201024049134N2. Efficacy of Tocilizumab in Hospitalized Patients with COVID-19: An open-label placebo-controlled clinical study. www.irct.ir/trial/56613 (first received 4 June 2021).
NCT04361552 {unpublished data only}
    1. NCT04361552. Tocilizumab for the treatment of cytokine release syndrome in patients with COVID-19 (SARS-CoV-2 infection). clinicaltrials.gov/ct2/show/NCT04361552 (First received April 22, 2020).
NCT04452474 {published data only}
    1. NCT04452474. Study of the efficacy and safety of a single administration of Olokizumab vs. placebo in addition to standard treatment in patients with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (COVID-19). clinicaltrials.gov/ct2/show/NCT04452474 (First received June 26, 2020).
NCT04494724 {unpublished data only}
    1. NCT04494724. Clazakizumab vs. placebo - COVID-19 infection. clinicaltrials.gov/ct2/show/NCT04494724 (first received 31 July 2020).
NCT05187793 {published data only}
    1. NCT05187793. Study of efficacy of different treatment regimens of Olokizumab (RESET). clinicaltrials.gov/ct2/show/NCT05187793 (First received December 24, 2021).

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