An open label trial of anakinra to prevent respiratory failure in COVID-19

Abstract

Background: It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19.

Methods: A total of 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100 mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied.

Results: 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95% CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata.

Conclusions: Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance.

Funding: This study was funded by the Hellenic Institute for the Study of Sepsis, Technomar Shipping Inc, Swedish Orphan Biovitrum, and the Horizon 2020 Framework Programme.

Clinical trial number: NCT04357366.

Keywords: COVID-19; SARS-CoV-2; anakinra; human; immunology; inflammation; interleukin-10; medicine; severe respiratory failure; suPAR.

Conflict of interest statement

EK, SM, NG, EK, MS, GL, AS, DP, SG, OT, VP, KT, MK, VL, MD, IP, KA, DM, AG, AS, TG, KK, TM, IT, KS, LC, SC, NV, CA, SC, MK No competing interests declared, PP honoraria from GILEAD Sciences, Janssen, and MSD, GD Advisor/Lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Novartis, Roche, Amgen, MSD, Janssen, Ipsen and Pfizer, has received Grant support from Bristol-Myers Squib, Gilead, Roche, Janssen, Abbvie and Bayer and was or is currently PI in National & International Protocols sponsored by Abbvie, Bristol-Myers Squibb, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Ipsen, Pfizer and Roche, GP independent educational grants from Pfizer, MSD, Angelini, and Biorad, HM honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier, Jv Senior editor, eLife, JE cofounder, shareholder and CSO of ViroGates A7S, Denmark and is named inventor on patents on suPAR owned by Copenhagen University Hospital Hvidovre, Denmark, MN supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. He has also received independent educational grants from TTxD, GSK and ViiV HealthCare, EG Reviewing editor, eLife

© 2021, Kyriazopoulou et al.

Figures

Figure 1.. Outcome of patients treated with anakinra.

(A) Curves of the cumulative incidence of severe respiratory failure (SRF); and (B) curves of 30-day mortality; the inset shows the curves in enlarged Y-axis. The analysis includes propensity-scored fully matched comparators treated with standard-of-care (SOC; n = 130) and the 130 participants in the SAVE trial who were treated with SOC treatment and anakinra (n = 130). Separate analysis for the cumulative incidence of SRF between the total available 179 comparators and the 130 participants in the SAVE trial can be found in Figure 1—figure supplement 1.

Figure 1—figure supplement 1.. Incidence of SRF among the total of 179 available comparators treated with SOC before matching and the 130 partiicpants in the SAVE trial treated with Anakinra and SOC.

Figure 2.. Effect of anakinra treatment on circulating mediators of patients with lower respiratory tract infection by SARS-CoV-2.

Concentrations of (A) suPAR (soluble urokinase plasminogen activator receptor); (B) the absolute lymphocyte count; (C) interleukin (IL)-6; and (D) sCD163 of patients under parallel standard-of-care (SOC) treatment (blue color) and of patients under treatment with SOC and anakinra (red color) at baseline (day of hospital admission) and day 7 of follow-up are shown. The concentrations of sIL-2R on day 7 are provided in panel E. Lines refer to median values. Comparisons between different groups were performed by the Mann–Whitney U-test and within the same group by the Wilcoxon test. Statistical comparisons: ns, non-significant; *p<0.05; **p<0.01; ***p<0.0001. The correlation of the IL-10/IL-6 ratio with the absolute change of the SOFA (sequential organ failure assessment) score on day 14 from the baseline is also shown (panel F). The Spearman rank of order correlation co-efficient and the p-value of the correlation is provided.

Figure 3.. Effect of anakinra treatment on cytokine production capacity from peripheral blood mononuclear cells (PBMCs).

PBMCs were isolated before and 7 days after start of treatment with anakinra. PBMCs were stimulated with lipopolysaccharide (LPS) of Escherichia coli O55:B5 for the production of interleukin (IL)−1β and with heat-killed Candida albicans for the production of IL-10. Production of IL-1β (panel A) and of IL-10 (panel B) is presented separately for patients who developed by day 14 severe respiratory failure (SRF) or not. Lines refer to median values. Comparisons between different groups were performed by the Mann–Whitney U-test and within the same group by the Wilcoxon test. Statistical comparisons: ns, non-significant; *p<0.05; **p<0.01. The correlation between the ratio of IL-10/IL-1β production by PBMCs and of the ratio of IL-10/IL-6 in serum on day 7 is provided in panel C. The Spearman rank of order correlation co-efficient and the p-value of the correlation is provided.

Figure 4.. Allocation of patients into the strata of the WHO clinical progression scale by day 28.

The analysis includes propensity-scored fully matched comparators treated with standard-of-care (SOC, n = 130) and the 130 participants in the SAVE trial who were treated with SOC treatment and anakinra (n = 130). Comparisons were done by the Pearson’s chi-square test.

Appendix 1—figure 1.. Trial profile and selection of parallel standard-of-care (SOC) comparators.

SOC comparators were hospitalized at the same time period at seven department of Internal Medicine in tertiary hospitals and they were selected in two steps: at the first step after application of the inclusion and exclusion criteria of patients receiving anakinra; and at the second step after propensity score matching. Abbreviations: APACHE II: acute physiology and chronic health evaluation; CCI: Charlson’s comorbidity index; COVID-19: infection by the new coronavirus SARS-CoV-2; ITT: intent-to-treat; LRTI: lower respiratory tract infection; PaO2/FiO2: respiratory fraction of partial oxygen pressure to fraction of inspired oxygen; PSI: pneumonia severity index; SOFA: sequential organ failure assessment; suPAR: soluble urokinase plasminogen activator receptor; WHO: severity classification of COVID-19 by the World Health organization.

Appendix 1—figure 2.. Survival curves until day 90.

Patients participating in the SAVE trial received standard-of-care (SOC) treatment and anakinra and were compared to parallel comparators treated only with SOC. The inset shows the curves in enlarged Y-axis. CI: confidence interval.

Appendix 1—figure 3.. Cost of hospitalization.

The three main categories of cost are shown: total cost, cost of anti-infectives, and cost of stay in the intensive care unit. Statistical comparisons between groups. ns: non-significant; *pAbbreviation: SOC: standard-of-care.