Factorial Randomized Trial of Rendesivir and Baricitinib Plus Dexamethasone for COVID-19 (the AMMURAVID Trial)
- Conditions
- Covid19
- Interventions
- Registration Number
- NCT04832880
- Lead Sponsor
- ASST Fatebenefratelli Sacco
- Brief 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)
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 4000
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Adults aged > 18 years able to provide a valid informed consent to the study
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Documented COVID-19 by direct testing (positive PCR), with lung infiltrates at imaging (Chest-X ray or CT) and requirement of oxygen supplementation
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Less than 10 days form symptoms onset
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Cytokine storm, using the criteria developed at Temple University (all of the three below criteria):
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CRP > 46 mg/l
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Ferritin > 250 ng/ml
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One variable of each of the three clusters below
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Cluster 1
- Albumin < 2.8 g/dl
- Lymphocytes <10.2 % of WBC
- Absolute neutrophil count > 11400/mm3
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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
-
-
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PaO2/FiO2 200-400 mmHg, while in oxygen therapy or continuous positive airway pressure (C-PAP)
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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:
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Orotracheal intubation or ECMO support
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Active solid / hematologic cancer (including invasive non-melanoma skin cancer)
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Hypersensitivity or contra-indications to one of the investigational agents (including history of deep vein thrombosis / pulmonary thromboembolism within 12 weeks prior to screening)
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Other active concurrent viral, fungal or bacterial infections (including active tuberculosis/latent TB treated for less than 4 weeks, HIV and HCV/HBV infections)
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Pregnancy/breastfeeding
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Incapability to provide a valid informed consent (including age < 18 years old)
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Heart failure with NYHA >= 2 or any acute cardiac or vascular event requiring therapy in the previous 12 months
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Chronic renal failure (baseline GFR < 45 ml/min*1.73m2)
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Liver cirrhosis moderate / severe (Child-Pugh B or C)
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Chronic respiratory failure requiring O2 therapy or ventilation therapy at home
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Blood neutrophils <1000/mcL, platelet <50000/mcL, Hb levels <80 g/l
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ALT/AST > 5 times UNL
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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)
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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)
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Use of any other investigational therapy for COVID-19 (including IV immunoglobulins, convalescent COVID-19 plasma or monoclonal antibodies)
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Impossibility to discontinue Strong inhibitors of OAT3 (such as probenecid) at study entry
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Any other condition judged by the local investigator as a contra-indication to eligibility
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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.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Baricitinib arm Baricitinib Oral Tablet [Olumiant] 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. Remdesivir + baricitinib arm Baricitinib Oral Tablet [Olumiant] 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. Control arm (dexamethasone arm) Dexamethasone IV dexamethasone 6 mg for 10 days Remdesivir arm Remdesivir IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10 Remdesivir arm Dexamethasone IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10 Baricitinib arm Dexamethasone 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. Remdesivir + baricitinib arm Remdesivir 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. Remdesivir + baricitinib arm Dexamethasone 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.
- Primary Outcome Measures
Name Time Method Prevention of very severe respiratory failure or mortality Day1-Day 28 Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 \<150 mmHg) or mortality
- Secondary Outcome Measures
Name Time Method Changes in PaO2 at arterial gas analysis Day 1-28 Course of PaO2 at arterial gas analysis and PaO2/FiO2
Changes in blood troponin T Day 1-28 Course of blood troponin T levels
Prevention of very severe respiratory failure or mortality Day 21 Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 \<150 mmHg) or mortality
Incidence of Adeverse Events Day 28 Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0)
Reduction of the requirements of orotracheal intubation/ECMO Day 1-28 Days with orotracheal intubation/ECMO
Velocity in clinical improvement Day 1-28 Time to clinical improvement (defined as one of the following: a) discharge, b) absent ventilator support with NEWS-2 score ≤3 and MELD ≤13)
Velocity in discharge Day 28 Proportion of discherged patients
Changes in blood ferritin Day 1-28 Course of blood ferritin levels
Changes in blood D-Dimer Day 1-28 Course of blood D-Dimer levels
Evolution of the NEWS-2 score Day 1-28 Course in the National Early Warning Score-2 score (0-20, with higher scores worse)
Changes in blood creatinine levels Day 1-28 Course of blood creatine levels
Changes in blood albumin Day 1-28 Course of blood albumin levels
Changes in blood CK Day 1-28 Course of blood CK levels
Fever disappearance Day 1-28 Time to persistent defervescence persistent defervescence (last day of T\<37.0°C, without recurrent T\>37.0° for at least 4 days)
Changes in periperal blood lymphocytes Day 1-28 Comparison of the course of lymphocytes counts at full blood counts among the treatment arm, as assessed by repeated measures analysis.
Changes in blood hemoglobin levels Day 1-28 Course of blood hemoglobin
Changes in blood ALT Day 1-28 Course of blood ALT levels
Changes in periperal blood neutrophils counts Day 1-28 Comparison of the course of neutrophils counts at full blood counts among the treatment arm, as assessed by repeated measures analysis.
Changes in blood LDH Day 1-28 Course of blood LDH levels
Changes in blood AST Day 1-28 Course of blood AST levels
Changes in blood IL-6 Day 1-28 Course of blood IL-6 levels
Changes in blood protrombine time (INR) Day 1-28 Course of blood protrombine time (INR)
Changes in blood HDL-colesterol Day 1-28 Course of blood HDL-colesterol levels
Prevention of mortality Day 1-28 Survival analysis
Prevention of very severe respiratory failure Day 1-28 Time to development very severe respiratory failure (PaO2/FiO2 \<150 mmHg)
Incidence of bacterial/fungal infections Day 28 Rate of bacterial/fungal infections
Evolution of the MELD score Day 1-28 Course in the Model for End-Stage Liver Disease score (scores \>=6, higher scores worse)
Changes in periperal blood leukocyte number Day 1-28 Course of periperal blood leukocyte number
Changes in periperal blood platelets Day 1-28 Comparison of the course of plateletscounts at full blood counts among the treatment arm, as assessed by repeated measures analysis.
Changes in blood bilirubin Day 1-28 Course of blood bilirubin levles
Changes in blood C-reactive protein Day 1-28 Course of blood C-reactive protein levels
Changes in PaO2/FiO2 Day 1-28 Course of PaO2/FiO2
Development of late complications 6 months Proportion of patients with FVC \< 70% of predicted, FEV1 \< 70% predicted and DLCO \< 80% predicted
Changes in blood triglycerides Day 1-28 Course of blood triglycerides levels
Changes in blood total colesterol Day 1-28 Course of blood total colesterol levels
Trial Locations
- Locations (21)
Ospedale di Ferrara
🇮🇹Ferrara, Italy
ASST Santi Paolo e Carlo
🇮🇹Milan, Italy
ASST Fatebenefratelli-Sacco
🇮🇹Milan, Italy
Ospedale San Salvatore
🇮🇹Pesaro, Italy
Azienda Ospedaliera Integrata -Verona
🇮🇹Verona, Italy
Policlinico Tor Vergata
🇮🇹Roma, Italy
Ospedale S Anna
🇮🇹Como, Italy
Ospedale di Legnago
🇮🇹Legnago, Italy
Ospedale di Udine
🇮🇹Udine, Italy
H Goretti
🇮🇹Latina, Italy
Ospedali Galliera
🇮🇹Genova, Italy
Ospedale di Legnano
🇮🇹Legnano, Italy
IRCCS San Raffaele
🇮🇹Milan, Italy
Ospedali di Prato e Pistoia
🇮🇹Prato, Italy
Ospedale SS Annunziata -Chieti
🇮🇹Chieti, Italy
Ospedali Riuniti delle Marche
🇮🇹Ancona, Italy
Ospedale Parini
🇮🇹Aosta, Italy
Ospedale di Firenze and Empoli
🇮🇹Firenze, Italy
Ospedale Manzoni
🇮🇹Lecco, Italy
Ospedale di Perugia
🇮🇹Perugia, Italy
Ospedale Cattinara e Maggiore
🇮🇹Trieste, Italy