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

• Status: Not yet recruiting
• Trial end date: 2022-12-01
• Target enrollment: 0
• Participant gender: All

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)

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: ASST Fatebenefratelli Sacco
• Treatments: Dexamethasone; Remdesivir

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.