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

Sponsor

ASST Fatebenefratelli Sacco (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04832880

Collaborator

(none)

4,000

Enrollment

Locations

Arms

19.8

Anticipated Duration (Months)

190.5

Patients Per Site

9.6

Patients Per Site Per Month

Study Details

Study Description

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)

Condition or Disease	Intervention/Treatment	Phase
Covid19	Drug: Baricitinib Oral Tablet [Olumiant] Drug: Remdesivir Drug: Dexamethasone	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

4000 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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.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.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Apr 6, 2021

Anticipated Primary Completion Date :

Mar 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Prevention of very severe respiratory failure or mortality [Day1-Day 28]
Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality

Secondary Outcome Measures

Prevention of mortality [Day 7]
Proportion of dead patients
Prevention of mortality [Day 14]
Proportion of dead patients
Prevention of mortality [Day 21]
Proportion of dead patients
Prevention of mortality [Day 28]
Proportion of dead patients
Prevention of mortality [Day 1-28]
Survival analysis
Prevention of very severe respiratory failure [Day 7]
Proportion of patients with PaO2/FiO2 <150 mmHg
Prevention of very severe respiratory failure [Day 14]
Proportion of patients with PaO2/FiO2 <150 mmHg
Prevention of very severe respiratory failure [Day 21]
Proportion of patients with PaO2/FiO2 <150 mmHg
Prevention of very severe respiratory failure [Day 28]
Proportion of patients with PaO2/FiO2 <150 mmHg
Prevention of very severe respiratory failure [Day 1-28]
Time to development very severe respiratory failure (PaO2/FiO2 <150 mmHg)
Prevention of very severe respiratory failure or mortality [Day 7]
Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality
Prevention of very severe respiratory failure or mortality [Day 14]
Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality
Prevention of very severe respiratory failure or mortality [Day 21]
Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality
Incidence of Adeverse Events [Day 7]
Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0)
Incidence of Adeverse Events [Day 14]
Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0)
Incidence of Adeverse Events [Day 21]
Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0)
Incidence of Adeverse Events [Day 28]
Proportion of number of AEs and SAEs (according to the Common Terminology Criteria for Adverse Events -CTCAE, Version 5.0)
Incidence of bacterial/fungal infections [Day 7]
Rate of bacterial/fungal infections
Incidence of bacterial/fungal infections [Day 14]
Rate of bacterial/fungal infections
Incidence of bacterial/fungal infections [Day 21]
Rate of bacterial/fungal infections
Incidence of bacterial/fungal infections [Day 28]
Rate of bacterial/fungal infections
Reduction of the requirements of orotracheal intubation/ECMO [Day 7]
Proportion of patients requiring orotracheal intubation/ECMO
Reduction of the requirements of orotracheal intubation/ECMO [Day 14]
Proportion of patients requiring orotracheal intubation/ECMO
Reduction of the requirements of orotracheal intubation/ECMO [Day 21]
Proportion of patients requiring orotracheal intubation/ECMO
Reduction of the requirements of orotracheal intubation/ECMO [Day 28]
Proportion of patients requiring orotracheal intubation/ECMO
Reduction of the requirements of orotracheal intubation/ECMO [Day 1-28]
Days with orotracheal intubation/ECMO
Evolution of the NEWS-2 score [Day 1-28]
Course in the National Early Warning Score-2 score (0-20, with higher scores worse)
Evolution of the MELD score [Day 1-28]
Course in the Model for End-Stage Liver Disease score (scores >=6, higher scores worse)
Velocity in clinical improvement [Day 1-28]
Time to clinical improvement (defined as one of the following: a) discharge, b) absent ventilator support with NEWS-2 score ≤3 and MELD ≤13)
Velocity in discharge [Day 1-28]
Time to discharge
Velocity in discharge [Day 7]
Proportion of discherged patients
Velocity in discharge [Day 14]
Proportion of discherged patients
Velocity in discharge [Day 21]
Proportion of discherged patients
Velocity in discharge [Day 28]
Proportion of discherged patients
Fever disappearance [Day 7]
Proportion of patients on persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days)
Fever disappearance [Day 14]
Proportion of patients on persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days)
Fever disappearance [Day 21]
Proportion of patients on persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days)
Fever disappearance [Day 28]
Proportion of patients on persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days)
Fever disappearance [Day 1-28]
Time to persistent defervescence persistent defervescence (last day of T<37.0°C, without recurrent T>37.0° for at least 4 days)
Changes in periperal blood leukocyte number [Day 1-28]
Course of periperal blood leukocyte number
Changes in periperal blood neutrophils counts [Day 1-28]
Comparison of the course of neutrophils counts at full blood counts among the treatment arm, as assessed by repeated measures analysis.
Changes in periperal blood lymphocytes [Day 1-28]
Comparison of the course of lymphocytes counts at full blood counts among the treatment arm, as assessed by repeated measures analysis.
Changes in periperal blood platelets [Day 1-28]
Comparison of the course of plateletscounts at full blood counts among the treatment arm, as assessed by repeated measures analysis.
Changes in blood hemoglobin levels [Day 1-28]
Course of blood hemoglobin
Changes in blood creatinine levels [Day 1-28]
Course of blood creatine levels
Changes in blood albumin [Day 1-28]
Course of blood albumin levels
Changes in blood bilirubin [Day 1-28]
Course of blood bilirubin levles
Changes in blood LDH [Day 1-28]
Course of blood LDH levels
Changes in blood AST [Day 1-28]
Course of blood AST levels
Changes in blood ALT [Day 1-28]
Course of blood ALT levels
Changes in blood CK [Day 1-28]
Course of blood CK levels
Changes in blood C-reactive protein [Day 1-28]
Course of blood C-reactive protein levels
Changes in blood IL-6 [Day 1-28]
Course of blood IL-6 levels
Changes in blood protrombine time (INR) [Day 1-28]
Course of blood protrombine time (INR)
Changes in blood ferritin [Day 1-28]
Course of blood ferritin levels
Changes in blood troponin T [Day 1-28]
Course of blood troponin T levels
Changes in blood triglycerides [Day 1-28]
Course of blood triglycerides levels
Changes in blood HDL-colesterol [Day 1-28]
Course of blood HDL-colesterol levels
Changes in blood total colesterol [Day 1-28]
Course of blood total colesterol levels
Changes in blood D-Dimer [Day 1-28]
Course of blood D-Dimer levels
Changes in PaO2 at arterial gas analysis [Day 1-28]
Course of PaO2 at arterial gas analysis and PaO2/FiO2
Changes in PaO2/FiO2 [Day 1-28]
Course of PaO2/FiO2
Development of late complications [6 months]
Death
Development of late complications [6 months]
New Hospital admissions
Development of late complications [6 months]
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
Development of late complications [6 months]
Proportion of patients with FVC < 70% of predicted, FEV1 < 70% predicted and DLCO < 80% predicted

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country
1	Ospedali Riuniti delle Marche	Ancona	Italy
2	Ospedale Parini	Aosta	Italy
3	Ospedale SS Annunziata -Chieti	Chieti	Italy
4	Ospedale S Anna	Como	Italy
5	Ospedale di Ferrara	Ferrara	Italy
6	Ospedale di Firenze and Empoli	Firenze	Italy
7	Ospedali Galliera	Genova	Italy
8	H Goretti	Latina	Italy
9	Ospedale Manzoni	Lecco	Italy
10	Ospedale di Legnago	Legnago	Italy
11	Ospedale di Legnano	Legnano	Italy
12	ASST Fatebenefratelli-Sacco	Milan	Italy
13	ASST Santi Paolo e Carlo	Milan	Italy
14	IRCCS San Raffaele	Milan	Italy
15	Ospedale di Perugia	Perugia	Italy
16	Ospedale San Salvatore	Pesaro	Italy
17	Ospedali di Prato e Pistoia	Prato	Italy
18	Policlinico Tor Vergata	Roma	Italy
19	Ospedale Cattinara e Maggiore	Trieste	Italy
20	Ospedale di Udine	Udine	Italy
21	Azienda Ospedaliera Integrata -Verona	Verona	Italy