Covid-19 Living Data

Trial NCT04330638; EudraCT2020-001500-41
Publication COV-AID - Declercq J, Lancet Respir Med (2021) (published paper)
Dates: 2020-04-04 to 2020-12-06
Funding: Public/non profit (Belgian Health Care Knowledge Center; VIB Grand Challenges (Flemish Institute for Biotechnology))
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Belgium Follow-up duration (days): 90
Inclusion criteria	older than 18 years had a laboratory proven diagnosis of COVID-19 with symptoms between 6 and 16 days a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2 P:F ratio) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen and bilateral pulmonary infiltrates either a single ferritin concentration measurement of more than 2000 μg/L at inclusion when they immediately required 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 (IU)/L, an increasing CRP concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL. If the patient had three of the previous criteria at hospital admission with lymphopenia of less than 800/μL, there was no need to document an increase over 24 h.
Exclusion criteria	mechanical ventilation for more than 24 h at randomisation a clinical frailty score greater than 3 before SARS-CoV-2 infection unlikelihood to survive beyond 48 h based on clinical assessment an active co-infection defined on clinical grounds (positive blood or sputum cultures) thrombocytopenia of less than 50 000/μL neutropenia of less than 1500/μL a history of bowel perforation or diverticulitis high dose systemic steroid or immunosuppressive drug use for a COVID-19-unrelated disorder.
Interventions
	Treatment Anakinra 100 mg once daily subcutaneously for 28 days or until hospital discharge Anakinra+Tocilizumab Anakinra 100 mg once daily subcutaneously for 28 days or until hospital discharge + Tocilizumab 8 mg/kg IV single dose (not exceeding 800 mg) Anakinra+Siltuximab Anakinra 100 mg once daily subcutaneously for 28 days or until hospital discharge + Siltuximab 11 mg/kg IV single dose Tocilizumab 8 mg/kg IV single dose (not exceeding 800 mg) Siltuximab 11 mg/kg IV single dose
	Control Standard care
Participants
	Randomized participants : Anakinra =43 Anakinra+Tocilizumab=32 Anakinra+Siltuximab=37 Tocilizumab=82 Siltuximab=76 Standard care=72
	Characteristics of participants N= 342 Mean age : NR 90 males Severity : Mild: n=1 / Moderate: n=58 / Severe: n=39 Critical: n=17 Number of vaccinated participants: NR
Primary outcome
	In the register Time to Clinical Improvement [Time Frame: at day 15]: defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the hospital: a) Death; b) Hospitalized, on invasive mechanical ventilation or ECMO; c) Hospitalized, on non-invasive ventilation or high flow oxygen devices; d) Hospitalized, requiring supplemental oxygen; e) Hospitalized, not requiring supplemental oxygen; f) Not hospitalized.
	In the report time to clinical improvement, defined as the time in days from randomisation until either an increase of at least two points on a 6-category ordinal scale (compared with the worst status at day of randomisation) or to discharge from the hospital alive, whichever occurred first. The 6-category ordinal scale was defined as 1=death; 2=hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 3=hospitalised, on non-invasive ventilation or high-flow oxygen devices; 4=hospitalised, requiring supplemental oxygen; 5=hospitalised, not requiring supplemental oxygen; 6=not hospitalised.
Documents available	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the study registry, supplementary material, protocol and statistical analysis plan were used in data extraction and risk of bias assessment. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group "Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis." JAMA. 2021;326(6):499-518 was also available. The study achieved the target sample size specified in the trial registry. There are no important changes from the trial registration in the primary outcome, procedures, intervention and control treatments. Total adverse events were not reported (but this had been pre-specified). 11% were critical at study start. Overall median age was 65 years (IQR 54–73) and 77% were male. Data presented for the outcomes mortality (D28), time to death, score 7 and above (D28), serious adverse events and clinical improvement (D28) (this last only for Tocilizumab and Siltuximab) were extracted from The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group "Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis." JAMA. 2021;326(6):499 518. The authors have been contacted in order to obtain the results.