Factorial Randomized Trial of Rendesivir and Baricitinib Plus Dexamethasone for COVID-19 (the AMMURAVID Trial) (AMMURAVID)
Covid19
About this trial
This is an interventional treatment trial for Covid19 focused on measuring remdesivir, baricitinib, dexamethasone
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.
Sites / Locations
- Ospedali Riuniti delle Marche
- Ospedale Parini
- Ospedale SS Annunziata -Chieti
- Ospedale S Anna
- Ospedale di Ferrara
- Ospedale di Firenze and Empoli
- Ospedali Galliera
- H Goretti
- Ospedale Manzoni
- Ospedale di Legnago
- Ospedale di Legnano
- ASST Fatebenefratelli-Sacco
- ASST Santi Paolo e Carlo
- IRCCS San Raffaele
- Ospedale di Perugia
- Ospedale San Salvatore
- Ospedali di Prato e Pistoia
- Policlinico Tor Vergata
- Ospedale Cattinara e Maggiore
- Ospedale di Udine
- Azienda Ospedaliera Integrata -Verona
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Experimental
Experimental
Experimental
Experimental
Control arm (dexamethasone arm)
Remdesivir arm
Baricitinib arm
Remdesivir + baricitinib arm
IV dexamethasone 6 mg for 10 days
IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10
IV dexamethasone 6 mg for 10 days + baricitinib 4 mg die for 10 days. For patients aged > 75 years or estimated GFR < 60 ml/min*1.73m2, baricitinib dose is reduced to 2 mg for 10 days.
IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10 + baricitinib 4 mg die for 10 days. For patients aged > 75 years or estimated GFR < 60 ml/min*1.73m2, baricitinib dose is reduced to 2 mg for 10 days.