An open prospective randomized therapeutic trial using ANAKINRA or TOCILIZUMAB alone or in combination with RUXOLITINIB in severe stage 2b and 3 COVID-19 disease

INTERVENTION: Trade Name: Kineret Pharmaceutical Form: Injection Trade Name: ROACTEMRA Pharmaceutical Form: Solution for infusion Trade Name: JAKAVI Pharmaceutical Form: Tablet CONDITION: COVID‐19‐associated disease Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] PRIMARY OUTCOME: Main Objective: Evaluate the therapeutic efficacy of anakinra or tocilizumab alone or in combination with ruxolitinib in severe (2b and 3) forms of COVID‐19.; The primary outcome criteria is ventilation free days at D28 (VFD28). Primary end point(s): ventilation free days at D28 (VFD28) (an increase of 5 days VFD28 is expected) Secondary Objective: Evaluate the therapeutic efficacy of anakinra or tocilizumab alone or in combination with ruxolitinib in severe (2b and 3) forms of COVID‐19 on:; Number of patients admitted in ICU (for stage 2b); Number of days in ICU (for stage 3) ; Death at D28 for all patients; Number of days in hospital; Time to oxygenation weaning; Visceral insufficiency improvement (SOFA score); Number of days without fever at D7 (without antipyretics for 48h); No increase in the number of bacteriamia or fungemia; Time to improvement of biological inflammatory markers (C reactive protein, fibrinogen, ferritinemia) ; Time to improvement of biological markers (blood cells counts, creatininemia, transaminases, LDH, gGT, coagulation tests) ; Improvement of blood cytokine concentrations and NLRP3 constituents; Blood concentrations of tocilizumab and search for acquired circulating anti‐tocilizumab inhibitory antibodies; Lung tomodensitometry and lung ventilation capacity evaluation at D90 after hospitalization exit; Timepoint(s) of evaluation of this end point: 28 days SECONDARY OUTCOME: Secondary end point(s): ‐Number of patients admitted in ICU (for stage 2b) ; ‐Number of days in ICU (for stage 3) ; ‐Death at D28 for all patients ; ‐Number of days in hospital ; ‐Visceral insufficiency improvement (SOFA score) ; ‐Number of days without fever at D7 (without antipyretics for 48h) ; ‐No increase in the number of bacterial or fungal sepsis ; ‐Biological parameters ; ‐Immunological parameters ; ‐Lung tomodensitometry and ventilation capacity ; Timepoint(s) of evaluation of this end point: 12 months INCLUSION CRITERIA: ‐Patients older than 18 and younger than 75, potentially eligible for admission in ICU ‐with proven infection with COVID19, using at least one positive pharyngeal polymerase chain reaction (PCR) test ‐COVID19 infection at stage 2b or 3 ‐Ability to provide informed consent signed by study patient or legally acceptable representative 1/ Stage 2b: hypoxemia necessitating oxygen therapy>5l/min in order to maintain SpO2>94% (in conventional hospitalization unit or ICU) and CRP>150 mg/l 2/ Stage 3: Moderate or severe ARDS necessitating invasive mechanical ventilation with a PaO2/FiO2<200 during more than 24hours 3/Etremely severe stage 3: a) very severe ARDS defined by invasive mechanical ventilation and requirement for veno‐venous extracorporeal membrane oxygenation (ECMO) b) or ARDS associated with at least on the following: ‐Shock with requirement for continuous IV adrenalin infusion>3mg/h ‐Myocarditis with cardiogenic