Covid19 Clinical Trial
— AMMURAVIDOfficial title:
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)
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. |
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 |
Lead Sponsor | Collaborator |
---|---|
ASST Fatebenefratelli Sacco |
Italy,
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 |
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