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Background: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome., Methods: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO 2 :FiO 2 ) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 μg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete., Findings: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups., Interpretation: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk., Funding: Belgian Health Care Knowledge Center and VIB Grand Challenges program., Competing Interests: Declaration of interests JD, KFAVD, BM, CB, VB, LH, LN, and EDL have received personal PhD training fellowships from FWO Flanders. SJT and LJMS have received personal postdoctoral fellowships from FWO Flanders and from the Ghent University BOF Fund. HA has received a postdoctoral personal training grant from VLAIO Flanders. US has received a grant from the European Respiratory Society. MH has received a grant from ULB Fonds Erasme on COVID-19 research, and an EU-Horizon DisCoVeRY trial grant and EU-Solid-Act trial grant on COVID-19 therapeutics; she received support for attending meetings from Pfizer and acts as the leader of the Sciensano committee, which produces the national guidelines on COVID-19 therapeutics. ND has received honoraria from Boehringer Ingelheim and support for attending meetings from Pfizer, Johnson & Johnson (J&J), and Merck Sharp & Dohme (MSD) and has served on a data and safety monitoring board (DSMB) for Roche. SA received research grants from Bristol-Myers Squibb (BMS)–Celgene and from European Hematology Association and consultancy fees from BMS–Celgene, J&J, Astellas, and Abbvie and honoraria from Pfizer and Astellas. JvdH received consultancy fess from Novartis and SOBI and honoraria from MSD, Sanofi, and J&J, and support for attending meetings from ViiV; he serves on DSMB boards for Novartis and SOBI. HS has received consultancy fees and support for attending meetings from Roche and Boehringer Ingelheim. CL has received consultancy fees from the sponsor Belgian Health Care Knowledge Center (KCE) to serve on the clinical trial board. MB owns stock of the International Drug Development Institute and Cluepoints. DS has received honoraria and support for attending meetings from AstraZeneca, Chiesi, GSK, Roche, and Merck. FB has received support from the Ghent University Hospital Clinical Research Fund. FHa has received a VIB Grand Challenge research grant, a Ghent University Special Research Fund (BOF) research grant, and a Ghent University Hospital Innovation Research Grant as well as lecture honoraria from CSL Behring. LV has received grants from University Hospital Ghent Innovation Fund, Research Foundation—Flanders–Strategic Basic Research (FWO-SBO) and FWO to do COVID-19 related research; he received consultancy fees and honoraria from Gilead and ViiV Healthcare. EvB received a grant from Ghent University Special Research Fund (BOF) and a research grant from ExeVir to do COVID-19 related research. She received honoraria from Gilead and is a member of the Sciensano committee, which produces the national guidelines on COVID-19 therapeutics. SR has received honoraria and meeting attendance support from BMS, MSD, Pfizer, Bayer, J&J, Astellas, Roche, and Ipsen; she serves on DSMBs organised by Pfizer, J&J, BMS, and MSD. IP has received research grants from FWO and honoraria from UCB Pharma and Galapagos. She serves on advisory boards from Abbvie, Amgen, Argenx, AstraZeneca, BMS, Galapagos, and Novartis. FHu is an employee of KCE The Belgian Healthcare Knowledge center, a public federal agency. BNL received an European Research Council Advanced Grant (ERC-2017-ADG-789384) and several FWO grants, as well as a University of Ghent Methusalem Grant. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)