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

ASST Fatebenefratelli Sacco4,000 enrolled

Overview

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)

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

4,000

Conditions

Covid19

Interventions

Baricitinib Oral Tablet [Olumiant]DRUG

Baricitinib 4 mg die (2 mg for patients aged \> 75 years) for 10 days.

RemdesivirDRUG

Intravenous remdesivir 200 mg on day 1, followed by remdesivir 100 mg die until day 10

DexamethasoneDRUG

Intravenous dexamethasone 6 mg for 10 days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (21)

Ospedali Riuniti delle Marche

Ancona, Italy

Ospedale Parini

Aosta, Italy

Outcomes

Primary Outcomes

Prevention of very severe respiratory failure or mortality

Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 \<150 mmHg) or mortality

Time frame: Day1-Day 28

Secondary Outcomes

Prevention of mortality

Proportion of dead patients

Time frame: Day 7

Prevention of mortality

Proportion of dead patients

Time frame: Day 14

Prevention of mortality

Proportion of dead patients

Time frame: Day 21

Prevention of mortality

Proportion of dead patients

Time frame: Day 28

Prevention of mortality

Survival analysis

Time frame: Day 1-28

Prevention of very severe respiratory failure

Proportion of patients with PaO2/FiO2 \<150 mmHg

Time frame: Day 7

Prevention of very severe respiratory failure

Proportion of patients with PaO2/FiO2 \<150 mmHg

Time frame: Day 14

Prevention of very severe respiratory failure

Proportion of patients with PaO2/FiO2 \<150 mmHg

Time frame: Day 21

Central Contacts

Enrico Tombetti, MD, PhD

CONTACT

3289098793 enrico.tombetti@unimi.it

Massimo Galli, Prof

CONTACT

3358058990 massimo.galli@unimi.it

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Ospedale SS Annunziata -Chieti

Ospedale S Anna

Como, Italy

Ospedale di Ferrara

Ferrara, Italy

Ospedale di Firenze and Empoli

Florence, Italy

Ospedali Galliera

Genova, Italy

H Goretti

Latina, Italy

Ospedale Manzoni

Lecco, Italy

Ospedale di Legnago

Legnago, Italy

...and 11 more locations

Prevention of very severe respiratory failure

Proportion of patients with PaO2/FiO2 \<150 mmHg

Time frame: Day 28

Prevention of very severe respiratory failure

Time to development very severe respiratory failure (PaO2/FiO2 \<150 mmHg)

Time frame: 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

Time frame: Day 7

Prevention of very severe respiratory failure or mortality

Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 \<150 mmHg) or mortality

Time frame: Day 14

Prevention of very severe respiratory failure or mortality

Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 \<150 mmHg) or mortality

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: Day 28

Incidence of bacterial/fungal infections

Rate of bacterial/fungal infections

Time frame: Day 7

Incidence of bacterial/fungal infections

Rate of bacterial/fungal infections

Time frame: Day 14

Incidence of bacterial/fungal infections

Rate of bacterial/fungal infections

Time frame: Day 21

Incidence of bacterial/fungal infections

Rate of bacterial/fungal infections

Time frame: Day 28

Reduction of the requirements of orotracheal intubation/ECMO

Proportion of patients requiring orotracheal intubation/ECMO

Time frame: Day 7

Reduction of the requirements of orotracheal intubation/ECMO

Proportion of patients requiring orotracheal intubation/ECMO

Time frame: Day 14

Reduction of the requirements of orotracheal intubation/ECMO

Proportion of patients requiring orotracheal intubation/ECMO

Time frame: Day 21

Reduction of the requirements of orotracheal intubation/ECMO

Proportion of patients requiring orotracheal intubation/ECMO

Time frame: Day 28

Reduction of the requirements of orotracheal intubation/ECMO

Days with orotracheal intubation/ECMO

Time frame: Day 1-28

Evolution of the NEWS-2 score

Course in the National Early Warning Score-2 score (0-20, with higher scores worse)

Time frame: Day 1-28

Evolution of the MELD score

Course in the Model for End-Stage Liver Disease score (scores \>=6, higher scores worse)

Time frame: 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)

Time frame: Day 1-28

Velocity in discharge

Time to discharge

Time frame: Day 1-28

Velocity in discharge

Proportion of discherged patients

Time frame: Day 7

Velocity in discharge

Proportion of discherged patients

Time frame: Day 14

Velocity in discharge

Proportion of discherged patients

Time frame: Day 21

Velocity in discharge

Proportion of discherged patients

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: Day 1-28

Changes in periperal blood leukocyte number

Course of periperal blood leukocyte number

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Day 1-28

Changes in blood hemoglobin levels

Course of blood hemoglobin

Time frame: Day 1-28

Changes in blood creatinine levels

Course of blood creatine levels

Time frame: Day 1-28

Changes in blood albumin

Course of blood albumin levels

Time frame: Day 1-28

Changes in blood bilirubin

Course of blood bilirubin levles

Time frame: Day 1-28

Changes in blood LDH

Course of blood LDH levels

Time frame: Day 1-28

Changes in blood AST

Course of blood AST levels

Time frame: Day 1-28

Changes in blood ALT

Course of blood ALT levels

Time frame: Day 1-28

Changes in blood CK

Course of blood CK levels

Time frame: Day 1-28

Changes in blood C-reactive protein

Course of blood C-reactive protein levels

Time frame: Day 1-28

Changes in blood IL-6

Course of blood IL-6 levels

Time frame: Day 1-28

Changes in blood protrombine time (INR)

Course of blood protrombine time (INR)

Time frame: Day 1-28

Changes in blood ferritin

Course of blood ferritin levels

Time frame: Day 1-28

Changes in blood troponin T

Course of blood troponin T levels

Time frame: Day 1-28

Changes in blood triglycerides

Course of blood triglycerides levels

Time frame: Day 1-28

Changes in blood HDL-colesterol

Course of blood HDL-colesterol levels

Time frame: Day 1-28

Changes in blood total colesterol

Course of blood total colesterol levels

Time frame: Day 1-28

Changes in blood D-Dimer

Course of blood D-Dimer levels

Time frame: Day 1-28

Changes in PaO2 at arterial gas analysis

Course of PaO2 at arterial gas analysis and PaO2/FiO2

Time frame: Day 1-28

Changes in PaO2/FiO2

Course of PaO2/FiO2

Time frame: Day 1-28

Development of late complications

Death

Time frame: 6 months

Development of late complications

New Hospital admissions

Time frame: 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

Time frame: 6 months

Development of late complications

Proportion of patients with FVC \< 70% of predicted, FEV1 \< 70% predicted and DLCO \< 80% predicted

Time frame: 6 months