Clinical trial NCT04832880: Factorial Randomized Trial of Rendesivir and Baricitinib Plus Dexamethasone for COVID-19 (the AMMURAVID Trial)
Official title: Factorial, Multicentric, Randomized Clinical Trial of Remdesivir and Immunotherapy in Combination With Dexamethasone for Moderate COVID-19 (the AMMURAVID Trial)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Covid19
Keywords: remdesivir
baricitinib
dexamethasone
Lead sponsor: ASST Fatebenefratelli Sacco
Sponsor class: OTHER
First posted: 2021-04-06
Enrollment: 4000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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)


Eligibility criteria: 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.

Primary outcomes:
measure: Prevention of very severe respiratory failure or mortality
timeFrame: Day1-Day 28
Secondary outcomes:
measure: Prevention of mortality
timeFrame: Day 7
measure: Prevention of mortality
timeFrame: Day 14
measure: Prevention of mortality
timeFrame: Day 21
measure: Prevention of mortality
timeFrame: Day 28
measure: Prevention of mortality
timeFrame: Day 1-28
measure: Prevention of very severe respiratory failure
timeFrame: Day 7
measure: Prevention of very severe respiratory failure
timeFrame: Day 14
measure: Prevention of very severe respiratory failure
timeFrame: Day 21
measure: Prevention of very severe respiratory failure
timeFrame: Day 28
measure: Prevention of very severe respiratory failure
timeFrame: Day 1-28
measure: Prevention of very severe respiratory failure or mortality
timeFrame: Day 7
measure: Prevention of very severe respiratory failure or mortality
timeFrame: Day 14
measure: Prevention of very severe respiratory failure or mortality
timeFrame: Day 21
measure: Incidence of Adeverse Events
timeFrame: Day 7
measure: Incidence of Adeverse Events
timeFrame: Day 14
measure: Incidence of Adeverse Events
timeFrame: Day 21
measure: Incidence of Adeverse Events
timeFrame: Day 28
measure: Incidence of bacterial/fungal infections
timeFrame: Day 7
measure: Incidence of bacterial/fungal infections
timeFrame: Day 14
measure: Incidence of bacterial/fungal infections
timeFrame: Day 21
measure: Incidence of bacterial/fungal infections
timeFrame: Day 28
measure: Reduction of the requirements of orotracheal intubation/ECMO
timeFrame: Day 7
measure: Reduction of the requirements of orotracheal intubation/ECMO
timeFrame: Day 14
measure: Reduction of the requirements of orotracheal intubation/ECMO
timeFrame: Day 21
measure: Reduction of the requirements of orotracheal intubation/ECMO
timeFrame: Day 28
measure: Reduction of the requirements of orotracheal intubation/ECMO
timeFrame: Day 1-28
measure: Evolution of the NEWS-2 score
timeFrame: Day 1-28
measure: Evolution of the MELD score
timeFrame: Day 1-28
measure: Velocity in clinical improvement
timeFrame: Day 1-28
measure: Velocity in discharge
timeFrame: Day 1-28
measure: Velocity in discharge
timeFrame: Day 7
measure: Velocity in discharge
timeFrame: Day 14
measure: Velocity in discharge
timeFrame: Day 21
measure: Velocity in discharge
timeFrame: Day 28
measure: Fever disappearance
timeFrame: Day 7
measure: Fever disappearance
timeFrame: Day 14
measure: Fever disappearance
timeFrame: Day 21
measure: Fever disappearance
timeFrame: Day 28
measure: Fever disappearance
timeFrame: Day 1-28
measure: Changes in periperal blood leukocyte number
timeFrame: Day 1-28
measure: Changes in periperal blood neutrophils counts
timeFrame: Day 1-28
measure: Changes in periperal blood lymphocytes
timeFrame: Day 1-28
measure: Changes in periperal blood platelets
timeFrame: Day 1-28
measure: Changes in blood hemoglobin levels
timeFrame: Day 1-28
measure: Changes in blood creatinine levels
timeFrame: Day 1-28
measure: Changes in blood albumin
timeFrame: Day 1-28
measure: Changes in blood bilirubin
timeFrame: Day 1-28
measure: Changes in blood LDH
timeFrame: Day 1-28
measure: Changes in blood AST
timeFrame: Day 1-28
measure: Changes in blood ALT
timeFrame: Day 1-28
measure: Changes in blood CK
timeFrame: Day 1-28
measure: Changes in blood C-reactive protein
timeFrame: Day 1-28
measure: Changes in blood IL-6
timeFrame: Day 1-28
measure: Changes in blood protrombine time (INR)
timeFrame: Day 1-28
measure: Changes in blood ferritin
timeFrame: Day 1-28
measure: Changes in blood troponin T
timeFrame: Day 1-28
measure: Changes in blood triglycerides
timeFrame: Day 1-28
measure: Changes in blood HDL-colesterol
timeFrame: Day 1-28
measure: Changes in blood total colesterol
timeFrame: Day 1-28
measure: Changes in blood D-Dimer
timeFrame: Day 1-28
measure: Changes in PaO2 at arterial gas analysis
timeFrame: Day 1-28
measure: Changes in PaO2/FiO2
timeFrame: Day 1-28
measure: Development of late complications
timeFrame: 6 months
measure: Development of late complications
timeFrame: 6 months
measure: Development of late complications
timeFrame: 6 months
measure: Development of late complications
timeFrame: 6 months
Other outcomes:
Locations:
city: Ancona
country: Italy
facility: Ospedali Riuniti delle Marche
city: Aosta
country: Italy
facility: Ospedale Parini
city: Chieti
country: Italy
facility: Ospedale SS Annunziata -Chieti
city: Como
country: Italy
facility: Ospedale S Anna
city: Ferrara
country: Italy
facility: Ospedale di Ferrara
city: Firenze
country: Italy
facility: Ospedale di Firenze and Empoli
city: Genova
country: Italy
facility: Ospedali Galliera
city: Latina
country: Italy
facility: H Goretti
city: Lecco
country: Italy
facility: Ospedale Manzoni
city: Legnago
country: Italy
facility: Ospedale di Legnago
city: Legnano
country: Italy
facility: Ospedale di Legnano
city: Milan
country: Italy
facility: ASST Fatebenefratelli-Sacco
city: Milan
country: Italy
facility: ASST Santi Paolo e Carlo
city: Milan
country: Italy
facility: IRCCS San Raffaele
city: Perugia
country: Italy
facility: Ospedale di Perugia
city: Pesaro
country: Italy
facility: Ospedale San Salvatore
city: Prato
country: Italy
facility: Ospedali di Prato e Pistoia
city: Roma
country: Italy
facility: Policlinico Tor Vergata
city: Trieste
country: Italy
facility: Ospedale Cattinara e Maggiore
city: Udine
country: Italy
facility: Ospedale di Udine
city: Verona
country: Italy
facility: Azienda Ospedaliera Integrata -Verona
Study officials:
affiliation: ASST Fatebenefratelli Sacco and Milan University
name: Massimo Galli, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: