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)


Eligibility Criteria:
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.