Factorial, Multicentric, Randomized Clinical Trial of Remdesivir and Immunotherapy in Combination With Dexamethasone for Moderate COVID-19 (the AMMURAVID Trial)
Trial Snapshot
- Phase
- Phase 3
- Sponsor
- ASST Fatebenefratelli Sacco
- Enrollment
- 4,000
- Locations
- 21
- Primary Endpoint
- Prevention of very severe respiratory failure or mortality
Study Overview
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)
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
Exclusion Criteria
- Not provided
Arms & Interventions
Control arm (dexamethasone arm)
IV dexamethasone 6 mg for 10 days
Intervention: Dexamethasone (Drug)
Remdesivir arm
IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10
Intervention: Remdesivir (Drug)
Remdesivir arm
IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10
Intervention: Dexamethasone (Drug)
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.
Intervention: Baricitinib Oral Tablet [Olumiant] (Drug)
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.
Intervention: Dexamethasone (Drug)
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.
Intervention: Baricitinib Oral Tablet [Olumiant] (Drug)
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.
Intervention: Remdesivir (Drug)
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.
Intervention: Dexamethasone (Drug)
Outcomes
Primary Outcomes
Prevention of very severe respiratory failure or mortality
Time Frame: Day1-Day 28
Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 \<150 mmHg) or mortality
Secondary Outcomes
- Prevention of very severe respiratory failure or mortality(Day 21)
- Incidence of Adeverse Events(Day 28)
- Reduction of the requirements of orotracheal intubation/ECMO(Day 1-28)
- Velocity in clinical improvement(Day 1-28)
- Velocity in discharge(Day 28)
- Changes in blood ferritin(Day 1-28)
- Evolution of the NEWS-2 score(Day 1-28)
- Changes in blood creatinine levels(Day 1-28)
- Changes in blood albumin(Day 1-28)
- Changes in blood CK(Day 1-28)
- Fever disappearance(Day 1-28)
- Changes in periperal blood lymphocytes(Day 1-28)
- Changes in blood hemoglobin levels(Day 1-28)
- Changes in blood ALT(Day 1-28)
- Changes in blood D-Dimer(Day 1-28)
- Changes in PaO2 at arterial gas analysis(Day 1-28)
- Changes in periperal blood neutrophils counts(Day 1-28)
- Changes in blood LDH(Day 1-28)
- Changes in blood AST(Day 1-28)
- Changes in blood IL-6(Day 1-28)
- Changes in blood protrombine time (INR)(Day 1-28)
- Changes in blood HDL-colesterol(Day 1-28)
- Prevention of mortality(Day 1-28)
- Prevention of very severe respiratory failure(Day 1-28)
- Incidence of bacterial/fungal infections(Day 28)
- Evolution of the MELD score(Day 1-28)
- Changes in periperal blood leukocyte number(Day 1-28)
- Changes in periperal blood platelets(Day 1-28)
- Changes in blood bilirubin(Day 1-28)
- Changes in blood C-reactive protein(Day 1-28)
- Changes in PaO2/FiO2(Day 1-28)
- Changes in blood troponin T(Day 1-28)
- Development of late complications(6 months)
- Changes in blood triglycerides(Day 1-28)
- Changes in blood total colesterol(Day 1-28)
Investigators
Enrico Tombetti
Assistant Professor
ASST Fatebenefratelli Sacco