factorial randomized trial of rendesivir and baricitinib plus dexamethasone for covid-19 (the ammuravid trial)

Conditions: Covid19

Summary: 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.

Keywords: remdesivir baricitinib dexamethasone