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

This is an interventional treatment trial for Covid19 focused on measuring remdesivir, baricitinib, dexamethasone Read More

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.