Factorial Randomized Trial of Rendesivir and Baricitinib Plus Dexamethasone for COVID-19 (the AMMURAVID Trial)

Inclusion Criteria:

• Adults aged > 18 years able to provide a valid informed consent to the study
• Documented COVID-19 by direct testing (positive PCR), with lung infiltrates at imaging (Chest-X ray or CT) and requirement of oxygen supplementation
• Less than 10 days form symptoms onset
• Cytokine storm, using the criteria developed at Temple University (all of the threebelow criteria):
• CRP > 46 mg/l
• Ferritin > 250 ng/ml
• One variable of each of the three clusters below
• Cluster 1
• Albumin < 2.8 g/dl
• Lymphocytes <10.2 % of WBC
• Absolute neutrophil count > 11400/mm3
• Cluster 2
• ALT > 60 U/L
• AST > 87 U/L
• D-dimers > 4930 µg/l fibrinogen-equivalent-units (FEU).
• LDH >416 U/L
• High sensitivity troponin > 1.09 ng/ml
• Cluster 3
• Anion Gap at arterial blood gas < 6.8 mM
• Chloride > 106 mM
• Potassium > 4.9 mM
• BUN:creatinine ratio > 29
• PaO2/FiO2 200-400 mmHg, while in oxygen therapy or continuous positive airway pressure (C-PAP)
• For women of childbearing potential and men: agreement to use contraception in thecase of heterosexual intercourses before day 28 with a failure rate < 1% per year (bilateral tubal ligation, male sterilisation, hormonal contraceptives inhibitingovulation, hormone-release or copper intrauterine devices). For men enrolled in thestudy, condom use is allowed.

Exclusion criteria:

• Orotracheal intubation or ECMO support
• Active solid / hematologic cancer (including invasive non-melanoma skin cancer)
• Hypersensitivity or contra-indications to one of the investigational agents (includinghistory of deep vein thrombosis / pulmonary thromboembolism within 12 weeks prior toscreening)
• Other active concurrent viral, fungal or bacterial infections (including activetuberculosis/latent TB treated for less than 4 weeks, HIV and HCV/HBV infections)
• Pregnancy/breastfeeding
• Incapability to provide a valid informed consent (including age < 18 years old)
• Heart failure with NYHA >= 2 or any acute cardiac or vascular event requiring therapyin the previous 12 months
• Chronic renal failure (baseline GFR < 45 ml/min*1.73m2)
• Liver cirrhosis moderate / severe (Child-Pugh B or C)
• Chronic respiratory failure requiring O2 therapy or ventilation therapy at home
• Blood neutrophils <1000/mcL, platelet <50000/mcL, Hb levels <80 g/l
• ALT/AST > 5 times UNL
• Use of any biologic agent or small molecule inhibitor and other investigational drugsin the previous 4 weeks or 5 half-lives (whichever is longer). Specific cut-offs forwash-out are required for the following therapies:
• B-cell targeted therapies: 24 weeks or 5 half-lives (whichever is longer)
• TNF-inhibitors: 2 weeks or 5 half-lives (whichever is longer)
• JAK-inhibitors: 1 week or 5 half-lives (whichever is longer)
• Use of other immunosuppressive agents in the last 3 months (chronic use of topicalsteroids and systemic steroids with a dose ≤5 mg of prednisone equivalents is allowed)
• Use of any other investigational therapy for COVID-19 (including IV immunoglobulins,convalescent COVID-19 plasma or monoclonal antibodies)
• Impossibility to discontinue Strong inhibitors of OAT3 (such as probenecid) at studyentry
• Any other condition judged by the local investigator as a contra-indication toeligibility
• Subjects who have received live vaccines within 4 weeks before the study or areplanned to receive live vaccine in the first months after study enrolment.