Treatment of COVID-19 Patients With Anti-interleukin Drugs
Condition: COVID-19
MeSH terms: COVID-19; Cytokine Release Syndrome
Intervention: Usual Care; Anakinra; Siltuximab; Tocilizumab
Intervention description: Usual Care; Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first; Siltuximab will be given via single IV infusion at a dose of 11 mg/kg; Tocilizumab will be given via single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection
Intervention MeSH terms: Siltuximab; Interleukin 1 Receptor Antagonist Protein
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Enrollment: 342.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Lung Injury; Hypoxia; Acute Respiratory Distress Syndrome; Corona virus; COVID-19; SARS (Severe Acute Respiratory Syndrome); Systemic Cytokine release Syndrome

Summary:

      The purpose of this study is to test the safety and effectiveness of individually or
      simultaneously blocking IL-6 and IL-1 versus standard of care on blood oxygenation and
      systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute
      hypoxic respiratory failure and systemic cytokine release syndrome
    

Eligibility criteria:

        Inclusion Criteria:

          -  Recent ( ≥ 6 days of flu-like symptoms or malaise yet ≤16 days of flu-like symptoms or
             malaise prior to randomization) infection with COVID-19.

          -  Confident COVID-19 diagnosis confirmed by antigen detection test and/or PCR and/or
             positive serology, or any emerging and validated diagnostic laboratory test for
             COVID-19 within this period.

          -  In some patients, it may be impossible to get a confident laboratory confirmation of
             COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or
             problems with diagnostic sensitivity. In those cases, in absence of an alternative
             diagnosis, and with highly suspect bilateral ground glass opacities on recent (<24h)
             chest-CT scan (confirmed by a radiologist and pulmonary physician as probable
             COVID-19), and a typical clinical and chemical diagnosis with signs of cytokine
             release syndrome, a patient can be enrolled as probable COVID-19 infected. In all
             cases, this needs confirmation by later seroconversion.

          -  Presence of hypoxia defined as PaO2/FiO2 below 350 while breathing room air in upright
             position or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high
             flow oxygen device or mechanical ventilation

          -  signs of cytokine release syndrome defined as ANY of the following:

               1. serum ferritin concentration >1000 mcg/L and rising since last 24h

               2. single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen
                  device or mechanical ventilation

               3. lymphopenia defined as <800 lymphocytes/microliter) and two of the following
                  extra criteria

                    -  Ferritin > 700 mcg/L and rising since last 24h

                    -  increased LDH (above 300 IU/L) and rising last 24h

                    -  D-Dimers > 1000 ng/mL and rising since last 24h

                    -  CRP above 70mg/L and rising since last 24h and absence of bacterial
                       infection

                    -  if three of the above are present at admission, no need to document 24h rise

          -  Chest X-ray or CT scan showing bilateral infiltrates within last 2 days

          -  Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients

          -  Age ≥ 18yrs

          -  Male or Female

          -  Willing and able to provide informed consent or legal representative willing to
             provide informed consent

        Exclusion Criteria:

          -  Patients with known history of serious allergic reactions, including anaphylaxis, to
             any of the study medications, or any component of the product.

          -  mechanical ventilation > 24 h at Randomization

          -  Patient on ECMO at time of screening

          -  clinical frailty scale above 3 (This frailty score is the patient status before first
             symptoms of COVID-19 episode.)

          -  active bacterial or fungal infection

          -  unlikely to survive beyond 48h

          -  neutrophil count below 1500 cells/microliter

          -  platelets below 50.000/microliter

          -  Patients enrolled in another investigational drug study

          -  patients on high dose systemic steroids (> 20 mg methylprednisolone or equivalent) for
             COVID-19 unrelated disorder

          -  patients on immunosuppressant or immunomodulatory drugs

          -  patients on current anti-IL1 or anti-IL6 treatment

          -  signs of active tuberculosis

          -  serum transaminase levels >5 times upper limit of normal

          -  bowel perforation or diverticulitis

          -  pregnant or breastfeeding females (all female subjects deemed of childbearing
             potential by the investigator must have negative pregnancy test at screening)

          -  Women of childbearing potential must have a negative serum pregnancy test pre-dose on
             day 1. Woùmen of childbearing potential must consistently and correctly use (during
             the entire treatment period and 3 months after last reatment) 1 highly effective
             method for contraception.