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

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

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 Overview

• Status: Not yet recruiting
• Conditions: Covid19
• Intervention / Treatment: Drug: Dexamethasone; Drug: Remdesivir; Drug: Baricitinib Oral Tablet [Olumiant]

• Study Type: Interventional
• Enrollment (Anticipated): 4000
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Enrico Tombetti, MD, PhD; Phone Number: +39 3289098793; Email: enrico.tombetti@unimi.it
• Study Contact Backup: Name: Massimo Galli, Prof; Phone Number: +39 3358058990; Email: massimo.galli@unimi.it

Study Locations

• Italy
  • Ancona, Italy
    • Ospedali Riuniti delle Marche
    • Contact: Marcello Tavio, Prof
    • Contact: marcello.tavio@ospedaliriuniti.marche.it
  • Aosta, Italy
    • Ospedale Parini
    • Contact: Magnani Silvia Carla Maria; Email: smagnani@ausl.vda.it
  • Chieti, Italy
    • Ospedale SS Annunziata -Chieti
    • Contact: Jacopo Vecchiet, Prof; Email: jacopo.vecchiet@unich.it
  • Como, Italy
    • Ospedale S Anna
    • Contact: Luigi Pusterla, MD; Email: luigi.pusterla@asst-lariana.it
  • Ferrara, Italy
    • Ospedale di Ferrara
    • Contact: Carlo Contini, Prof; Email: cnc@unife.it
  • Firenze, Italy
    • Ospedale di Firenze and Empoli
    • Contact: Massimo Di Pietro, MD; Email: massimo.dipietro@uslcentro.toscana.it
  • Genova, Italy
    • Ospedali Galliera
    • Contact: Emanuele Pontali, MD; Email: emanuele.pontali@galliera.it
  • Latina, Italy
    • H Goretti
    • Contact: Miriam Lichtner, Prof; Email: miriam.lichtner@uniroma1.it
  • Lecco, Italy
    • Ospedale Manzoni
    • Contact: Stefania Piconi, MD; Email: s.piconi@asst-lecco.it
  • Legnago, Italy
    • Ospedale di Legnago
    • Contact: Pierangelo Rovere, MD; Email: pierangelo.rovere@aulss9.veneto.it
  • Legnano, Italy
    • Ospedale di Legnano
    • Contact: Stefano Rusconi, Prof; Email: stefano.rusconi@unimi.it
  • Milan, Italy
    • IRCCS San Raffaele
    • Contact: Antonella Castagna, Prof; Email: castagna.antonella@hsr.it
  • Milan, Italy
    • ASST Santi Paolo e Carlo
  • Milan, Italy
    • Asst Fatebenefratelli-Sacco
    • Contact: Massimo Galli, Prof; Email: massimo.galli@unimi.it
  • Perugia, Italy
    • Ospedale di Perugia
    • Contact: Andrea Tosti, MD; Email: andrea.tosti@ospedale.perugia.it
  • Pesaro, Italy
    • Ospedale San Salvatore
    • Contact: Francesco, MD; Email: francesco.barchiesi@ospedalimarchenord.it
  • Prato, Italy
    • Ospedali di Prato e Pistoia
    • Contact: Pierluigi Blanc, MD; Email: pierluigi.blanc@uslcentro.toscana.it
  • Roma, Italy
    • Policlinico Tor Vergata
    • Contact: Massimo Andreoni, Prof; Email: andreoni@uniroma2.it
  • Trieste, Italy
    • Ospedale Cattinara e Maggiore
    • Contact: Roberto Luzzati; Email: roberto.luzzati@asugi.sanita.fvg.it
  • Udine, Italy
    • Ospedale di Udine
    • Contact: Carlo Tascini, Prof; Email: carlo.tascini@asufc.sanita.fvg.it
  • Verona, Italy
    • Azienda Ospedaliera Integrata -Verona
    • Contact: Evelina Tacconelli, Prof; Phone Number: +39 3497790711; Email: evelina.tacconelli@univr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ASST Fatebenefratelli Sacco
• Investigators: Principal Investigator: Massimo Galli, MD, PhD, ASST Fatebenefratelli Sacco and Milan University

Study record dates

Study Major Dates

• Study Start (Anticipated): April 6, 2021
• Primary Completion (Anticipated): March 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: October 12, 2020
• First Submitted That Met QC Criteria: April 3, 2021
• First Posted (Actual): April 6, 2021

Study Record Updates

• Last Update Posted (Actual): April 6, 2021
• Last Update Submitted That Met QC Criteria: April 3, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: dexamethasone; baricitinib; remdesivir
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-Inflammatory Agents; Antimetabolites; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Remdesivir
• Other Study ID Numbers: The AMMURAVID trial; 2020-001854-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

IPD Plan Description

The e-CRF platform (Cloud-R) ensures data protection and satisties all quality requirements for data management and protection of patients confidentiality.

Confidential data will be available only for physicians in charge of individual patients.

Anonymized data will be made available to other research upon written request accompanied with a motivation and a scientific rationale

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No