Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: [RCT], 2021, Kyriazopoulou et al

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

(SAVE-MORE trial)

Evdoxia Kyriazopoulou, Garyfallia Poulakou, Haralampos Milionis, Simeon Metallidis, Georgios Adamis, Konstantinos Tsiakos, Archontoula Fragkou, Aggeliki Rapti, Christina Damoulari, Massimo Fantoni, Ioannis Kalomenidis, Georgios Chrysos, Andrea Angheben, Ilias Kainis, Zoi Alexiou, Francesco Castelli, Francesco Saverio Serino, Maria Tsilika, Petros Bakakos, Emanuele Nicastri, Vassiliki Tzavara, Evangelos Kostis, Lorenzo Dagna, Panagiotis Koufargyris, Katerina Dimakou, Spyridon Savvanis, Glykeria Tzatzagou, Maria Chini, Giulio Cavalli, Matteo Bassetti, Konstantina Katrini, Vasileios Kotsis, George Tsoukalas, Carlo Selmi, Ioannis Bliziotis, Michael Samarkos, Michael Doumas, Sofia Ktena, Aikaterini Masgala, Ilias Papanikolaou, Maria Kosmidou, Dimitra-Melia Myrodia, Aikaterini Argyraki, Chiara Simona Cardellino, Katerina Koliakou, Eleni-Ioanna Katsigianni, Vassiliki Rapti, Efthymia Giannitsioti, Antonella Cingolani, Styliani Micha, Karolina Akinosoglou, Orestis Liatsis-Douvitsas, Styliani Symbardi, Nikolaos Gatselis, Maria Mouktaroudi, Giuseppe Ippolito, Eleni Florou, Antigone Kotsaki, Mihai G. Netea, Jesper Eugen-Olsen, Miltiades Kyprianou, Periklis Panagopoulos, George N. Dalekos, Evangelos J. Giamarellos-Bourboulis

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.

Link | PDF (Nature Medicine) [Open Access]

 

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They studied respiratory failure, not really long COVID here, but there will be a study of the same medication, anakinra, for long COVID, based on what they learned from this study.

Germany, Greece, Italy, Spain: Safety and Efficacy of Anakinra Treatment for Patients With Post Acute Covid Syndrome (PRECISION)

After the end of the SAVE-MORE trial, the understanding of the immune activation of PACS and the development of tools for the evaluation of patients have become the main aims of the Hellenic Institute for the study of sepsis (HISS) group. More precisely, patients with medical history of COVID-19 pneumonia during three separate time periods and matched comparators for age, sex, comorbidities, and state of vaccination were followed up and evaluated for PACS. Main findings can be summarized as follows:

1. For at least one year after acute COVID-19 there is considerable immune dysregulation involving both the innate and the adaptive responses.
2. Patients with PACS may be classified into four main phenotype clusters: fatigue involving 70.8%, respiratory cluster involving 33.2%, systemic symptoms involving 17.7% and other symptoms involving 26.1%.
3. The risk for progression into PACS was significantly lower among patients treated with anakinra in the acute stage (odds ratio 0.59, p: 0.017) showing a role of IL-1 for the progression into PACS.
4. Patients with fatigue bring distinct immunotype compared to the respiratory cluster.
5. IP-10 (interferon-gamma-induced protein-10) at levels more than 250 pg/ml has sensitivity 99.3%, specificity 90.9%, positive predictive value (PPV) 97.9% and negative predictive value (NPV) 97.6% for the diagnosis of the post acute COVID immune dysregulation.

PRECISION is a proof-of-concept, randomized clinical trial (RCT) aiming to evaluate the efficacy and safety of anakinra in patients with PACS in improving the clinical and immunological state over 4 to 8 weeks as measured by a composite endpoint, namely, the "Score of PACS progression reversal".