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

Study Overview
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Brief Summary
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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)

Official Title
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Factorial, Multicentric, Randomized Clinical Trial of Remdesivir and Immunotherapy in Combination With Dexamethasone for Moderate COVID-19 (the AMMURAVID Trial)

Conditions
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Covid19

Intervention / Treatment
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* Drug: Baricitinib Oral Tablet [Olumiant]
* Drug: Remdesivir
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control arm (dexamethasone arm)<br>IV dexamethasone 6 mg for 10 days | Drug: Dexamethasone<br>* Intravenous dexamethasone 6 mg for 10 days<br>|
| Experimental: Remdesivir arm<br>IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10 | Drug: Remdesivir<br>* Intravenous remdesivir 200 mg on day 1, followed by remdesivir 100 mg die until day 10<br>* Other names: Veklury;Drug: Dexamethasone<br>* Intravenous dexamethasone 6 mg for 10 days<br>|
| Experimental: Baricitinib arm<br>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. | Drug: Baricitinib Oral Tablet [Olumiant]<br>* Baricitinib 4 mg die (2 mg for patients aged > 75 years) for 10 days.<br>* Other names: Olumiant;Drug: Dexamethasone<br>* Intravenous dexamethasone 6 mg for 10 days<br>|
| Experimental: Remdesivir + baricitinib arm<br>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. | Drug: Baricitinib Oral Tablet [Olumiant]<br>* Baricitinib 4 mg die (2 mg for patients aged > 75 years) for 10 days.<br>* Other names: Olumiant;Drug: Remdesivir<br>* Intravenous remdesivir 200 mg on day 1, followed by remdesivir 100 mg die until day 10<br>* Other names: Veklury;Drug: Dexamethasone<br>* Intravenous dexamethasone 6 mg for 10 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention of very severe respiratory failure or mortality | Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality | Day1-Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention of mortality | Proportion of dead patients | Day 7 | 
| Prevention of mortality | Proportion of dead patients | Day 14 | 
| Prevention of mortality | Proportion of dead patients | Day 21 | 
| Prevention of mortality | Proportion of dead patients | Day 28 | 
| Prevention of mortality | Survival analysis | Day 1-28 | 
| Prevention of very severe respiratory failure | Proportion of patients with PaO2/FiO2 <150 mmHg | Day 7 | 
| Prevention of very severe respiratory failure | Proportion of patients with PaO2/FiO2 <150 mmHg | Day 14 | 
| Prevention of very severe respiratory failure | Proportion of patients with PaO2/FiO2 <150 mmHg | Day 21 | 
| Prevention of very severe respiratory failure | Proportion of patients with PaO2/FiO2 <150 mmHg | Day 28 | 
| Prevention of very severe respiratory failure | Time to development very severe respiratory failure (PaO2/FiO2 <150 mmHg) | Day 1-28 | 
| Prevention of very severe respiratory failure or mortality | Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality | Day 7 | 
| Prevention of very severe respiratory failure or mortality | Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality | Day 14 | 
| Prevention of very severe respiratory failure or mortality | Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality | Day 21 | 
| Incidence of Adeverse Events | Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0) | Day 7 | 
| Incidence of Adeverse Events | Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0) | Day 14 | 
| Incidence of Adeverse Events | Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0) | Day 21 | 
| Incidence of Adeverse Events | Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0) | Day 28 | 
| Incidence of bacterial/fungal infections | Rate of bacterial/fungal infections | Day 7 | 
| Incidence of bacterial/fungal infections | Rate of bacterial/fungal infections | Day 14 | 
| Incidence of bacterial/fungal infections | Rate of bacterial/fungal infections | Day 21 | 
| Incidence of bacterial/fungal infections | Rate of bacterial/fungal infections | Day 28 | 
| Reduction of the requirements of orotracheal intubation/ECMO | Proportion of patients requiring orotracheal intubation/ECMO | Day 7 | 
| Reduction of the requirements of orotracheal intubation/ECMO | Proportion of patients requiring orotracheal intubation/ECMO | Day 14 | 
| Reduction of the requirements of orotracheal intubation/ECMO | Proportion of patients requiring orotracheal intubation/ECMO | Day 21 | 
| Reduction of the requirements of orotracheal intubation/ECMO | Proportion of patients requiring orotracheal intubation/ECMO | Day 28 | 
| Reduction of the requirements of orotracheal intubation/ECMO | Days with orotracheal intubation/ECMO | Day 1-28 | 
| Evolution of the NEWS-2 score | Course in the National Early Warning Score-2 score (0-20, with higher scores worse) | Day 1-28 | 
| Evolution of the MELD score | Course in the Model for End-Stage Liver Disease score (scores >=6, higher scores worse) | Day 1-28 | 
| Velocity in clinical improvement | Time to clinical improvement (defined as one of the following: a) discharge, b) absent ventilator support with NEWS-2 score ≤3 and MELD ≤13) | Day 1-28 | 
| Velocity in discharge | Time to discharge | Day 1-28 | 
| Velocity in discharge | Proportion of discherged patients | Day 7 | 
| Velocity in discharge | Proportion of discherged patients | Day 14 | 
| Velocity in discharge | Proportion of discherged patients | Day 21 | 
| Velocity in discharge | Proportion of discherged patients | Day 28 | 
| Fever disappearance | Proportion of patients on persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days) | Day 7 | 
| Fever disappearance | Proportion of patients on persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days) | Day 14 | 
| Fever disappearance | Proportion of patients on persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days) | Day 21 | 
| Fever disappearance | Proportion of patients on persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days) | Day 28 | 
| Fever disappearance | Time to persistent defervescence persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days) | Day 1-28 | 
| Changes in periperal blood leukocyte number | Course of periperal blood leukocyte number | Day 1-28 | 
| Changes in periperal blood neutrophils counts | Comparison of the course of neutrophils counts at full blood counts among the treatment arm, as assessed by repeated measures analysis. | Day 1-28 | 
| Changes in periperal blood lymphocytes | Comparison of the course of lymphocytes counts at full blood counts among the treatment arm, as assessed by repeated measures analysis. | Day 1-28 | 
| Changes in periperal blood platelets | Comparison of the course of plateletscounts at full blood counts among the treatment arm, as assessed by repeated measures analysis. | Day 1-28 | 
| Changes in blood hemoglobin levels | Course of blood hemoglobin | Day 1-28 | 
| Changes in blood creatinine levels | Course of blood creatine levels | Day 1-28 | 
| Changes in blood albumin | Course of blood albumin levels | Day 1-28 | 
| Changes in blood bilirubin | Course of blood bilirubin levles | Day 1-28 | 
| Changes in blood LDH | Course of blood LDH levels | Day 1-28 | 
| Changes in blood AST | Course of blood AST levels | Day 1-28 | 
| Changes in blood ALT | Course of blood ALT levels | Day 1-28 | 
| Changes in blood CK | Course of blood CK levels | Day 1-28 | 
| Changes in blood C-reactive protein | Course of blood C-reactive protein levels | Day 1-28 | 
| Changes in blood IL-6 | Course of blood IL-6 levels | Day 1-28 | 
| Changes in blood protrombine time (INR) | Course of blood protrombine time (INR) | Day 1-28 | 
| Changes in blood ferritin | Course of blood ferritin levels | Day 1-28 | 
| Changes in blood troponin T | Course of blood troponin T levels | Day 1-28 | 
| Changes in blood triglycerides | Course of blood triglycerides levels | Day 1-28 | 
| Changes in blood HDL-colesterol | Course of blood HDL-colesterol levels | Day 1-28 | 
| Changes in blood total colesterol | Course of blood total colesterol levels | Day 1-28 | 
| Changes in blood D-Dimer | Course of blood D-Dimer levels | Day 1-28 | 
| Changes in PaO2 at arterial gas analysis | Course of PaO2 at arterial gas analysis and PaO2/FiO2 | Day 1-28 | 
| Changes in PaO2/FiO2 | Course of PaO2/FiO2 | Day 1-28 | 
| Development of late complications | Death | 6 months | 
| Development of late complications | New Hospital admissions | 6 months | 
| Development of late complications | Proportion of patients developing new medical conditions in each interventional arm as compared to the control arm. Specific focus to: new-onset interstitial lung disease new onset respiratory failure requiring O2 therapy or ventilation therapy at home thromboembolic event ischemic events (stroke, acute coronary syndromes, pe-ripheral ischemias) arterial hypertension | 6 months | 
| Development of late complications | Proportion of patients with FVC < 70% of predicted, FEV1 < 70% predicted and DLCO < 80% predicted | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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remdesivir, baricitinib, dexamethasone