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

NCT04832880 | Unknown Phase 3 DMC

• 2 other identifiers: The AMMURAVID trial2020-001854-23
• Study Type: interventional
• Target: 4,000
• Locations: 1 country
• Sites: 21

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

Keywords

remdesivir; baricitinib; dexamethasone

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (66)

• Prevention of mortality

  Day 7

• Prevention of mortality

  Day 14

• Prevention of mortality

  Day 21

• Prevention of mortality

  Day 28

• Prevention of mortality

  Day 1-28

Study Arms (4)

Control arm (dexamethasone arm)

EXPERIMENTAL

IV dexamethasone 6 mg for 10 days

Drug: Dexamethasone

Remdesivir arm

EXPERIMENTAL

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

Drug: Remdesivir; Drug: Dexamethasone

Baricitinib arm

EXPERIMENTAL

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]; Drug: Dexamethasone

Remdesivir + baricitinib arm

EXPERIMENTAL

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]; Drug: Remdesivir; Drug: Dexamethasone

Interventions

Baricitinib Oral Tablet [Olumiant] DRUG

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

Also known as: Olumiant

Baricitinib arm; Remdesivir + baricitinib arm

Remdesivir DRUG

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

Also known as: Veklury

Remdesivir + baricitinib arm; Remdesivir arm

Dexamethasone DRUG

Intravenous dexamethasone 6 mg for 10 days

Baricitinib arm; Control arm (dexamethasone arm); Remdesivir + baricitinib arm; Remdesivir arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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)

Sponsors & Collaborators

• ASST Fatebenefratelli Sacco: lead

Study Sites (21)

Ospedali Riuniti delle Marche

Ancona, Italy

Location

Ospedale Parini

Aosta, Italy

Location

Ospedale SS Annunziata -Chieti

Chieti, Italy

Location

Ospedale S Anna

Como, Italy

Location

Ospedale di Ferrara

Ferrara, Italy

Location

Ospedale di Firenze and Empoli

Florence, Italy

Location

Ospedali Galliera

Genova, Italy

Location

H Goretti

Latina, Italy

Location

Ospedale Manzoni

Lecco, Italy

Location

Ospedale di Legnago

Legnago, Italy

Location

Ospedale di Legnano

Legnano, Italy

Location

ASST Fatebenefratelli-Sacco

Milan, Italy

Location

ASST Santi Paolo e Carlo

Milan, Italy

Location

IRCCS San Raffaele

Milan, Italy

Location

Ospedale di Perugia

Perugia, Italy

Location

Ospedale San Salvatore

Pesaro, Italy

Location

Ospedali di Prato e Pistoia

Prato, Italy

Location

Policlinico Tor Vergata

Roma, Italy

Location

Ospedale Cattinara e Maggiore

Trieste, Italy

Location

Ospedale di Udine

Udine, Italy

Location

Azienda Ospedaliera Integrata -Verona

Verona, Italy

Location

MeSH Terms

Conditions

COVID-19

Interventions

baricitinib; remdesivir; Dexamethasone

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Massimo Galli, MD, PhD

  ASST Fatebenefratelli Sacco and Milan University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Enrico Tombetti, MD, PhD

CONTACT

3289098793; enrico.tombetti@unimi.it

Massimo Galli, Prof

CONTACT

3358058990; massimo.galli@unimi.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: 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.

Study Record Dates

• First Submitted: October 12, 2020
• First Posted: April 6, 2021
• Study Start: April 6, 2021
• Primary Completion: March 1, 2022
• Study Completion: December 1, 2022
• Last Updated: April 6, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (21)