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

Covid19 Clinical Trial

— AMMURAVID  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04832880
• Other study ID #: The AMMURAVID trial
• Secondary ID: 2020-001854-23
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: April 6, 2021
• Est. completion date: December 2022

Study information

• Verified date: April 2021
• Source: ASST Fatebenefratelli Sacco
• Contact: Enrico Tombetti, MD, PhD
• Phone: 3289098793
• Email: enrico.tombetti[@]unimi.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 4000
• Est. completion date: December 2022
• Est. primary completion date: March 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Covid19

Intervention

Drug:
• Baricitinib Oral Tablet [Olumiant]
Baricitinib 4 mg die (2 mg for patients aged > 75 years) for 10 days.
• Remdesivir
Intravenous remdesivir 200 mg on day 1, followed by remdesivir 100 mg die until day 10
• Dexamethasone
Intravenous dexamethasone 6 mg for 10 days

Locations

Country	Name	City	State
Italy	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	Firenze
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

Sponsors (1)

Lead Sponsor	Collaborator
ASST Fatebenefratelli Sacco

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Prevention of mortality	Proportion of dead patients	Day 7
Secondary	Prevention of mortality	Proportion of dead patients	Day 14
Secondary	Prevention of mortality	Proportion of dead patients	Day 21
Secondary	Prevention of mortality	Proportion of dead patients	Day 28
Secondary	Prevention of mortality	Survival analysis	Day 1-28
Secondary	Prevention of very severe respiratory failure	Proportion of patients with PaO2/FiO2 <150 mmHg	Day 7
Secondary	Prevention of very severe respiratory failure	Proportion of patients with PaO2/FiO2 <150 mmHg	Day 14
Secondary	Prevention of very severe respiratory failure	Proportion of patients with PaO2/FiO2 <150 mmHg	Day 21
Secondary	Prevention of very severe respiratory failure	Proportion of patients with PaO2/FiO2 <150 mmHg	Day 28
Secondary	Prevention of very severe respiratory failure	Time to development very severe respiratory failure (PaO2/FiO2 <150 mmHg)	Day 1-28
Secondary	Prevention of very severe respiratory failure or mortality	Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality	Day 7
Secondary	Prevention of very severe respiratory failure or mortality	Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality	Day 14
Secondary	Prevention of very severe respiratory failure or mortality	Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality	Day 21
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Incidence of bacterial/fungal infections	Rate of bacterial/fungal infections	Day 7
Secondary	Incidence of bacterial/fungal infections	Rate of bacterial/fungal infections	Day 14
Secondary	Incidence of bacterial/fungal infections	Rate of bacterial/fungal infections	Day 21
Secondary	Incidence of bacterial/fungal infections	Rate of bacterial/fungal infections	Day 28
Secondary	Reduction of the requirements of orotracheal intubation/ECMO	Proportion of patients requiring orotracheal intubation/ECMO	Day 7
Secondary	Reduction of the requirements of orotracheal intubation/ECMO	Proportion of patients requiring orotracheal intubation/ECMO	Day 14
Secondary	Reduction of the requirements of orotracheal intubation/ECMO	Proportion of patients requiring orotracheal intubation/ECMO	Day 21
Secondary	Reduction of the requirements of orotracheal intubation/ECMO	Proportion of patients requiring orotracheal intubation/ECMO	Day 28
Secondary	Reduction of the requirements of orotracheal intubation/ECMO	Days with orotracheal intubation/ECMO	Day 1-28
Secondary	Evolution of the NEWS-2 score	Course in the National Early Warning Score-2 score (0-20, with higher scores worse)	Day 1-28
Secondary	Evolution of the MELD score	Course in the Model for End-Stage Liver Disease score (scores >=6, higher scores worse)	Day 1-28
Secondary	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
Secondary	Velocity in discharge	Time to discharge	Day 1-28
Secondary	Velocity in discharge	Proportion of discherged patients	Day 7
Secondary	Velocity in discharge	Proportion of discherged patients	Day 14
Secondary	Velocity in discharge	Proportion of discherged patients	Day 21
Secondary	Velocity in discharge	Proportion of discherged patients	Day 28
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Changes in periperal blood leukocyte number	Course of periperal blood leukocyte number	Day 1-28
Secondary	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
Secondary	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
Secondary	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
Secondary	Changes in blood hemoglobin levels	Course of blood hemoglobin	Day 1-28
Secondary	Changes in blood creatinine levels	Course of blood creatine levels	Day 1-28
Secondary	Changes in blood albumin	Course of blood albumin levels	Day 1-28
Secondary	Changes in blood bilirubin	Course of blood bilirubin levles	Day 1-28
Secondary	Changes in blood LDH	Course of blood LDH levels	Day 1-28
Secondary	Changes in blood AST	Course of blood AST levels	Day 1-28
Secondary	Changes in blood ALT	Course of blood ALT levels	Day 1-28
Secondary	Changes in blood CK	Course of blood CK levels	Day 1-28
Secondary	Changes in blood C-reactive protein	Course of blood C-reactive protein levels	Day 1-28
Secondary	Changes in blood IL-6	Course of blood IL-6 levels	Day 1-28
Secondary	Changes in blood protrombine time (INR)	Course of blood protrombine time (INR)	Day 1-28
Secondary	Changes in blood ferritin	Course of blood ferritin levels	Day 1-28
Secondary	Changes in blood troponin T	Course of blood troponin T levels	Day 1-28
Secondary	Changes in blood triglycerides	Course of blood triglycerides levels	Day 1-28
Secondary	Changes in blood HDL-colesterol	Course of blood HDL-colesterol levels	Day 1-28
Secondary	Changes in blood total colesterol	Course of blood total colesterol levels	Day 1-28
Secondary	Changes in blood D-Dimer	Course of blood D-Dimer levels	Day 1-28
Secondary	Changes in PaO2 at arterial gas analysis	Course of PaO2 at arterial gas analysis and PaO2/FiO2	Day 1-28
Secondary	Changes in PaO2/FiO2	Course of PaO2/FiO2	Day 1-28
Secondary	Development of late complications	Death	6 months
Secondary	Development of late complications	New Hospital admissions	6 months
Secondary	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
Secondary	Development of late complications	Proportion of patients with FVC < 70% of predicted, FEV1 < 70% predicted and DLCO < 80% predicted	6 months