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

 In the current worldwide medical emergency, a rapid identification of effective therapeutic
 strategy is crucial. So far, therapy with dexamethasone, remdesivir and baricitinib have been
 associated with evidence of impact on the clinical impact on COVID-19, but the effect of
 baricitinib and remdesivir in combination with dexamethasone.

 The AAMMURAVID trial is endorced and supported by the Italian Regulatory agency (AIFA-Agenzia
 Italiana del Farmaco)
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 three
 below 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 the
 case of heterosexual intercourses before day 28 with a failure rate < 1% per year
 (bilateral tubal ligation, male sterilisation, hormonal contraceptives inhibiting
 ovulation, hormone-release or copper intrauterine devices). For men enrolled in the
 study, 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 (including
 history of deep vein thrombosis / pulmonary thromboembolism within 12 weeks prior to
 screening)

 -  Other active concurrent viral, fungal or bacterial infections (including active
 tuberculosis/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 therapy
 in 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 drugs
 in the previous 4 weeks or 5 half-lives (whichever is longer). Specific cut-offs for
 wash-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 topical
 steroids 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 study
 entry

 -  Any other condition judged by the local investigator as a contra-indication to
 eligibility

 -  Subjects who have received live vaccines within 4 weeks before the study or are
 planned to receive live vaccine in the first months after study enrolment.