Covid19
Conditions
Keywords
remdesivir, baricitinib, dexamethasone
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)
Interventions
Baricitinib 4 mg die (2 mg for patients aged \> 75 years) for 10 days.
DRUGRemdesivir
Intravenous remdesivir 200 mg on day 1, followed by remdesivir 100 mg die until day 10
DRUGDexamethasone
Intravenous dexamethasone 6 mg for 10 days
Sponsors
ASST Fatebenefratelli Sacco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Factorial design with four-stages (K=4). Three interim analyses are pre-planned. At each stage, the use of remdesivir and/or baricitinib might be suspended due to futility or ef-ficacy. Overall, we will accept a two-sided alpha error of alpha=0.05 and a beta error of β=0.10.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Prevention of very severe respiratory failure | Day 7 | Proportion of patients with PaO2/FiO2 \<150 mmHg |
| Prevention of very severe respiratory failure or mortality | Day 7 | Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 \<150 mmHg) or mortality |
| Incidence of Adeverse Events | Day 7 | Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0) |
| Incidence of bacterial/fungal infections | Day 7 | Rate of bacterial/fungal infections |
| Reduction of the requirements of orotracheal intubation/ECMO | Day 7 | Proportion of patients requiring orotracheal intubation/ECMO |
| Evolution of the NEWS-2 score | Day 1-28 | Course in the National Early Warning Score-2 score (0-20, with higher scores worse) |
| Evolution of the MELD score | Day 1-28 | Course in the Model for End-Stage Liver Disease score (scores \>=6, higher scores worse) |
| 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 1-28 | Time to discharge |
| Fever disappearance | Day 7 | Proportion of patients on persistent defervescence (last day of T\<37.0°C, without recurrent T\>37.0° for at least 4 days) |
| Changes in periperal blood leukocyte number | Day 1-28 | Course of periperal blood leukocyte number |
| 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 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 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 hemoglobin levels | Day 1-28 | Course of blood hemoglobin |
| 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 |
| Prevention of mortality | Day 7 | Proportion of dead patients |
| 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 ALT | Day 1-28 | Course of blood ALT levels |
| Changes in blood CK | Day 1-28 | Course of blood CK levels |
| Changes in blood C-reactive protein | Day 1-28 | Course of blood C-reactive protein 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 ferritin | Day 1-28 | Course of blood ferritin levels |
| Changes in blood troponin T | Day 1-28 | Course of blood troponin T levels |
| Changes in blood triglycerides | Day 1-28 | Course of blood triglycerides levels |
| Changes in blood HDL-colesterol | Day 1-28 | Course of blood HDL-colesterol levels |
| Changes in blood total colesterol | Day 1-28 | Course of blood total colesterol levels |
| Changes in blood D-Dimer | Day 1-28 | Course of blood D-Dimer levels |
| Changes in PaO2 at arterial gas analysis | Day 1-28 | Course of PaO2 at arterial gas analysis and PaO2/FiO2 |
| Changes in PaO2/FiO2 | Day 1-28 | Course of PaO2/FiO2 |
| Development of late complications | 6 months | Death |
| Changes in blood bilirubin | Day 1-28 | Course of blood bilirubin levles |
Countries
Italy
Contacts
Primary ContactEnrico Tombetti, MD, PhD
Backup ContactMassimo Galli, Prof
Outcome results
None listed