Interleukin-1 blocking agents for treating COVID-19

Mauricia Davidson, Sonia Menon, Anna Chaimani, Theodoros Evrenoglou, Lina Ghosn, Carolina Graña, Nicholas Henschke, Elise Cogo, Gemma Villanueva, Gabriel Ferrand, Carolina Riveros, Hillary Bonnet, Philipp Kapp, Conor Moran, Declan Devane, Joerg J Meerpohl, Gabriel Rada, Asbjørn Hróbjartsson, Giacomo Grasselli, David Tovey, Philippe Ravaud, Isabelle Boutron, Mauricia Davidson, Sonia Menon, Anna Chaimani, Theodoros Evrenoglou, Lina Ghosn, Carolina Graña, Nicholas Henschke, Elise Cogo, Gemma Villanueva, Gabriel Ferrand, Carolina Riveros, Hillary Bonnet, Philipp Kapp, Conor Moran, Declan Devane, Joerg J Meerpohl, Gabriel Rada, Asbjørn Hróbjartsson, Giacomo Grasselli, David Tovey, Philippe Ravaud, Isabelle Boutron

Abstract

Background: Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19.

Objectives: To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19. We will update this assessment regularly.

Search methods: We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021).

Selection criteria: We included randomised controlled trials (RCTs) evaluating IL-1 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity.

Data collection and analysis: We followed Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 28; ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28; ≥ D60); all-cause mortality (D28; ≥ D60); incidence of any adverse events; and incidence of serious adverse events.

Main results: We identified four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab. Effectiveness of anakinra for people with COVID-19 Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence. The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence). The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence). Safety of anakinra for people with COVID-19 Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence). The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence). Effectiveness of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence). The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence). The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence). Safety of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence). The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence).

Authors' conclusions: Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com).

Trial registration: ClinicalTrials.gov NCT04330638.

Conflict of interest statement

Mauricia Davidson: none known.

Sonia Menon: works as systematic reviewer for p95 consultancy company.

Anna Chaimani: none known.

Theodoros Evrenoglou: none known.

Lina Ghosn: none known.

Carolina Graña: none known.

Nicholas Henschke: is employed by Cochrane Response, an evidence consultancy initiative from Cochrane. Cochrane Response was commissioned by the WHO to perform work on the living systematic review and living network meta‐analysis for COVID‐19 studies.

Elise Cogo: is employed by Cochrane Response, an evidence consultancy initiative from Cochrane. Cochrane Response was commissioned by the WHO to perform work on the living systematic review and living network meta‐analysis for COVID‐19 studies.

Gemma Villanueva: is employed by Cochrane Response, an evidence consultancy initiative from Cochrane. Cochrane Response was commissioned by the WHO to perform work on the living systematic review and living network meta‐analysis for COVID‐19 studies.

Gabriel Ferrand: none known.

Carolina Riveros: none known.

Philipp Kapp: none known.

Hillary Bonnet: none known.

Conor Moran: none known.

Declan Devane: works for Cochrane Ireland and Evidence Synthesis Ireland which are funded within the National University of Ireland Galway (Ireland) by the Health Research Board (HRB) and the Health and Social Care, Research and Development (HSC R&D) Division of the Public Health Agency in Northern Ireland.

Joerg J Meerpohl: reports funding from the Federal Ministry of Health and the Federal Ministry of Education and Research.

Gabriel Rada: none known.

Asbjørn Hróbjartsson: none known.

Giacomo Grasselli: receives personal fees for lectures from Getinge, Fisher&Paykel, Draeger Medical, Biotest, Thermofisher and MSD; support for travel‐meeting expenses from Biotest and Getinge (all outside the present work). GG also received an unrestricted research grant from Fisher&Paykel (unrelated to the present work).

David Tovey: has a part‐time paid consultancy with the Université de Paris.

Philippe Ravaud: is a minority shareholder of INATO. PR was the methodologist of the CORIMUNO‐19 platform which generated the Mariette CORIMUNO‐19 Collaborative 2021 trial. PR did not undertake any inclusion decisions/data extraction or risk of bias assessments for the Mariette CORIMUNO‐19 Collaborative 2021 trial.

Isabelle Boutron: is director of Cochrane France and co‐convenor of the Cochrane Bias methods group.