Treatment of COVID-19 patients with anti-interleukin drugs

INTERVENTION: Trade Name: Kineret Product Name: Kineret Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: ANAKINRA CAS Number: 143090‐92‐0 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Trade Name: RoActemra Product Name: RoActemra Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: TOCILIZUMAB CAS Number: 375823‐41‐9 Other descriptive name: TOCILIZUMAB Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 20‐ Trade Name: RoActemra Product Name: RoActemra Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: TOCILIZUMAB CAS Number: 375823‐41‐9 Other descriptive name: TOCILIZUMAB Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 162‐ Trade Name: SYLVANT Product Name: SYLVANT Pharmaceutical Form: Powder for concentrate for solution for infusion INN or Proposed INN: Siltuximab CAS Number: 541502‐14‐1 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 400‐ CONDITION: COVID‐19 patients with acute hypoxic respiratory failure and systemic cytokine release syndrome. Therapeutic area: Diseases [C] ‐ Virus Diseases [C02] PRIMARY OUTCOME: Main Objective: Study if blockade of IL‐6 +/‐ IL‐1 to block the cytokine storm and acute lung injury in comparison with usual care reduces time to clinical improvement as defined by an increase of more than 2 on the 6 point ordinal scale or discharge from the hospital Primary end point(s): Time to clinical improvement (defined as the time from randomization to either an improvement of two points on a six‐category ordinal scale measured daily till day 28 or discharge from the hospital or death); 1. Death; 2. Hospitalized, on invasive mechanical ventilation or ECMO;; 3. Hospitalized, on non‐invasive ventilation or high flow oxygen devices;; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen; 6. Not hospitalized Secondary Objective: ‐to investigate whether treatment with either tocilizumab, siltuximab, anakinra or combinations thereof; ‐improves oxygenation; ‐causes defervescence, measured as time to first fever‐free 48h period; ‐improves features of secondary haemophagocytic lymphohistiocytosis; ‐improves features of secondary haemophagocytic lymphohistiocytosis in relation to serum IL‐6 and IL‐1; ‐affects clinical outcome in relation to IL‐6 and IL‐1 levels; ‐affects the rate of nosocomial infection; ‐affects progression to mechanical ventilation, high oxygen delivery device, and/or ARDS in non‐ventilated patients; ‐affects length of dependency of ventilation in ventilated patients; ‐affects all‐cause mortality rate at 4 and 20 weeks post inclusion; ‐affects long term 10‐20 week follow up clinical status and lung function; ‐is safe (number of AEs/SAEs); ‐When there is a significant association between IL‐6 blockade and time to clinical improvement, tocilizumab and siltuximab will be compared versus usual care Timepoint(s) of evaluation of this end point: 28 days SECONDARY OUTCOME: Secondary end point(s): ‐Time since randomization until improvement in oxygenation, defined as independence from supplemental oxygen ; ‐Mean change in oxygenation defined by Pa02/FiO2 while breathing room air between day 1 and day 15 (or hospital discharge, whichever is first) ; ‐Number of days with hypoxia ; ‐Number of days of supplemental oxygen use ; ‐Time since randomization until absence of fever for more than 48h without antipyretics ; ‐Number of days with fever ; ‐Time since randomization until halving of CRP levels compared to peak value during trial ; ‐Time since randomization until halving of ferritin levels compared to peak value during trial ; ‐Incidence of AEs/SAEs during 28 days ; ‐Duration of hospital stay ; ‐Duration of hospital stay in survivors ; ‐Mean change in clinical sign score between day 1 and day 7 and between day 1 and day 15 (or on discharge, whichever is first) ; ‐Time since randomization until clinical sign score <6 maintained for 24h ; ‐Mean change of SOFA score between day 1 and day 7 or between day 1 and day 15 (or on discharge, whichever is first) ; ‐Mean change NEWS2 score between day 1 and day 7 or between day 1 and day 15 (or on discharge, whichever is first) ; ‐Time since randomization until NEWS2 score less than 2 for at least 24h ; ‐ Percentage of patients reporting each severity rating on a 6‐point ordinal scale ; 6‐point Ordinal Scale at 15 days, in relation to serum IL‐1 and IL‐6 ; ‐ Incidence of nosocomial bacterial or invasive fungal infection for 28 days after enrolment in trial ; ‐ incidence of secondary haemophagocytic lymphohistiocytosis defined by Hs score ; Cardinal features of sHLH include unremitting fever, cytopenias, hyperferritinaemia, hypertriglyceridemia, pulmonary involvement can present as ARDS. Hs score calculation see http://saintantoine.aphp.fr/score/ ; ‐Incidence of secondary haemophagocytic lymphohistiocytosis defined by Hs score (Hs score calculation see http://saintantoine.aphp.fr/score/) in relation to serum IL‐1 and IL‐6 ; ‐Time since randomization until first use of high‐flow oxygen devices, non‐invasive or invasive mechanical ventilation in non‐ventilated patients ; ‐Time since randomization until first use of salvage systemic steroids in ventilated patients ; ‐Ventilator‐free days over 28 days from inclusion date ; ‐Duration of mechanical ventilation in ventilated patients ; ‐Duration of ICU stay in patients that enrolled in trial while already on invasive or non‐invasive mechanical ventilation ; ‐Time to progression to ARDS in ventilated patients ; criteria‐defined ARDS (according to the American‐European Consensus Conference (AECC) diagnostic criteria for ARDS: acute onset; ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) of 200mmHg or less, regardless of positive end‐expiratory pressure; bilateral infiltrates seen on frontal chest radiograph; and pulmonary artery wedge pressure of 18 mm Hg or less when measured, or no clinical evidence of left atrial hypertension) ; ‐Time to progression to ARDS in ventilated patients according to IL‐1 and IL‐6 ; ‐All‐cause mortality rate at 28 days post inclusion (excluding group that entered during ventilation) ; ‐Percentage of patients in clinical status on 6‐point Ordinal Scale at 10‐20 weeks follow up ; ‐Incidence of lung function abnormalities at 10‐20 weeks follow up ; ‐Incidence of lung fibrosis on chest CT scan at 10‐20 weeks follow up ; ‐All cause mortality at 20 weeks post inclusion for the entire study population Timepoint(s) of evaluation of this end point: 24h ; day 7 ; day 15 ; 28 days after enrolment ; 12‐20 weeks follow up ; 20 weeks post inclusion INCLUSION CRITERIA: ‐Recent (=6 days of flu‐like symptoms or malaise yet =16 days of flu‐like symptoms or malaise prior to randomization) infection with COVID‐19.Confident COVID‐19 diagnosis confirmed by antigen detection test and/or PCR and/or positive serology, or any emerging and validated diagnostic laboratory test for COVID‐19 within this period. ‐In some patients, it may be impossible to get a confident laboratory confirmation of COVID‐19 diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (<24h) chest‐CT scan (confirmed by a radiologist and pulmonary physician as probable COVID‐19), and a typical clinical and chemical diagnosis with signs of cytokine release syndrome, a patient can be enrolled as probable COVID‐19 infected. In all cases, this needs confir