Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial

Abstract

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml−1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26–0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.

Calming the cytokine storm in COVID-19

“…In this issue of Nature Medicine, Kyriazopoulou et al report their evaluation of blockade of the cytokine IL-1 via the recombinant human IL-1 receptor antagonist anakinra in patients with COVID-19 6 . Almost 600 patients with COVID-19 pneumonia who were at risk for respiratory failure, as defined by an elevated serum level of soluble urokinase-type plasminogen activator receptor (suPAR), were randomly assigned to receive either anakinra or placebo (along with standard of care) early during hospitalization, before they needed mechanical ventilation.…”

The Effect of Anakinra in Hospitalized Patients with COVID-19: An Updated Systematic Review and Meta-Analysis

“…Most studies were non-randomized observational studies designed to compare the standard of care treatment plus anakinra versus the standard of care treatment alone [20,[22][23][24]. One study was randomized but not placebo controlled [21] and only one study was a placebo controlled double-blind trial [25]. Interestingly, in one observational study both early and late anakinra administration were investigated [24].…”

“…Finally, after a website search, the first placebo-controlled randomized trial on the effect of anakinra in hospitalized COVID-19 patients was identified, at a preprint version at the time of the search [25].…”

“…The meta-analysis of the six included studies (n = 1553, weighted age 64 years, male sex 66%, treated with anakinra 50%, intubated 3%) showed a pooled hazard ratio for death in patients treated with anakinra versus those who did not receive anakinra at 0.47 (95% confidence intervals [CI] 0.34, 0.65) (Figure 1). A 28-day mortality was the endpoint of interest in the majority of studies [20][21][22]25]. Most patients had moderate to severe COVID-19 (Table 1).…”

“…Three sensitivity analyses were performed for robustness: (1) after excluding the only randomized placebo-controlled trial [25], the pooled adjusted hazard ratio remained the same at 0.47 (95% CI 0.33, 0.68); (2) after excluding the two randomized studies (a placebocontrolled and one standard of care-controlled study) [21,25], the pooled adjusted hazard ratio was similar at 0.42 (95% CI 0.28, 0.63); (3) after excluding a study that seemed to differ significantly from the others both in terms of percentage of intubated patients (33%) and in terms of the hazard ratio for mortality (0.18) [20], the pooled adjusted hazard ratio was 0.53 (95% CI 0.37, 0.74). A multivariate meta-regression analysis did not reveal any significant associations between the mean age (regression coefficient [RC] 0.17, 95% CI −0.19, 0.53), percentage of males (RC −0.05, 95% CI −0.33, 0.23), mean baseline C-reactive protein levels of the patients receiving anakinra (RC 0.001, 95% CI −0.04, 0.04), and mean time of administration since symptoms onset (RC 0.01, 95% CI −0.40, 0.42) among the included studies and the hazard ratios for death (all p > 0.10).…”