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

NCT ID: NCT04832880

Last Updated: 2021-04-06

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 4000 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-06
• Study Completion Date: 2022-12-31

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)

Conditions

Covid19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Control arm (dexamethasone arm)

IV dexamethasone 6 mg for 10 days

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

Intravenous dexamethasone 6 mg for 10 days

Remdesivir arm

IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10

Group Type: EXPERIMENTAL

Remdesivir

Intervention Type: DRUG

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

Dexamethasone

Intervention Type: DRUG

Intravenous dexamethasone 6 mg for 10 days

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.

Group Type: EXPERIMENTAL

Baricitinib Oral Tablet [Olumiant]

Intervention Type: DRUG

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

Dexamethasone

Intervention Type: DRUG

Intravenous dexamethasone 6 mg for 10 days

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.

Group Type: EXPERIMENTAL

Baricitinib Oral Tablet [Olumiant]

Intervention Type: DRUG

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

Remdesivir

Intervention Type: DRUG

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

Dexamethasone

Intervention Type: DRUG

Intravenous dexamethasone 6 mg for 10 days

Interventions

Baricitinib Oral Tablet [Olumiant]

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

Intervention Type: DRUG

Remdesivir

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

Intervention Type: DRUG

Dexamethasone

Intravenous dexamethasone 6 mg for 10 days

Intervention Type: DRUG

Other Intervention Names

Olumiant; Veklury

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ASST Fatebenefratelli Sacco

OTHER

Sponsor Role: lead

Responsible Party

Enrico Tombetti

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Massimo Galli, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

ASST Fatebenefratelli Sacco and Milan University

Locations

Ospedali Riuniti delle Marche

Ancona, , Italy

Ospedale Parini

Aosta, , Italy

Ospedale SS Annunziata -Chieti

Chieti, , Italy

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

Ospedale di Legnano

Legnano, , Italy

ASST Fatebenefratelli-Sacco

Milan, , Italy

ASST Santi Paolo e Carlo

Milan, , Italy

IRCCS San Raffaele

Milan, , Italy

Ospedale di Perugia

Perugia, , Italy

Ospedale San Salvatore

Pesaro, , Italy

Ospedali di Prato e Pistoia

Prato, , Italy

Policlinico Tor Vergata

Roma, , Italy

Ospedale Cattinara e Maggiore

Trieste, , Italy

Ospedale di Udine

Udine, , Italy

Azienda Ospedaliera Integrata -Verona

Verona, , Italy

Countries

Italy

Central Contacts

Enrico Tombetti, MD, PhD

Role: CONTACT

enrico.tombetti@unimi.it

3289098793 ext. +39

Massimo Galli, Prof

Role: CONTACT

massimo.galli@unimi.it

3358058990 ext. +39

Facility Contacts

Marcello Tavio, Prof

Role: primary

marcello.tavio@ospedaliriuniti.marche.it

Role: backup

Magnani Silvia Carla Maria

Role: primary

smagnani@ausl.vda.it

Jacopo Vecchiet, Prof

Role: primary

jacopo.vecchiet@unich.it

Luigi Pusterla, MD

Role: primary

luigi.pusterla@asst-lariana.it

Carlo Contini, Prof

Role: primary

cnc@unife.it

Massimo Di Pietro, MD

Role: primary

massimo.dipietro@uslcentro.toscana.it

Emanuele Pontali, MD

Role: primary

emanuele.pontali@galliera.it

Miriam Lichtner, Prof

Role: primary

miriam.lichtner@uniroma1.it

Stefania Piconi, MD

Role: primary

s.piconi@asst-lecco.it

Pierangelo Rovere, MD

Role: primary

pierangelo.rovere@aulss9.veneto.it

Stefano Rusconi, Prof

Role: primary

stefano.rusconi@unimi.it

Massimo Galli, Prof

Role: primary

massimo.galli@unimi.it

Antonella D'arminio monforte, Prof

Role: primary

antonella.darminio@unimi.it

Antonella Castagna, Prof

Role: primary

castagna.antonella@hsr.it

Andrea Tosti, MD

Role: primary

andrea.tosti@ospedale.perugia.it

Francesco, MD

Role: primary

francesco.barchiesi@ospedalimarchenord.it

Pierluigi Blanc, MD

Role: primary

pierluigi.blanc@uslcentro.toscana.it

Massimo Andreoni, Prof

Role: primary

andreoni@uniroma2.it

Roberto Luzzati

Role: primary

roberto.luzzati@asugi.sanita.fvg.it

Carlo Tascini, Prof

Role: primary

carlo.tascini@asufc.sanita.fvg.it

Evelina Tacconelli, Prof

Role: primary

evelina.tacconelli@univr.it

3497790711 ext. +39

Other Identifiers

2020-001854-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

The AMMURAVID trial

Identifier Type: -

Identifier Source: org_study_id