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
There are currently no treatments directed at halting the cytokine storm and acute lung
injury to stop the progression from manageable hypoxia to frank respiratory failure and ARDS
in patients with COVID-19 infection. Preventing progression from early acute hypoxia and
cytokine release syndrome to frank hypoxic respiratory failure and ARDS could have a huge
impact on the foreseeable overflow of the ICU units. In ventilated patients, preventing the
onset of ARDS, or shortening ICU stay could also be crucial in this regard.
The clinical status after 15 days treatment is evaluated to measure the effectiveness of
tocilizumab, tocilizumab and anakinra, siltuximab, siltuximab and anakinra and anakinra on
restoring lung homeostasis,using single IV injection (siltuximab or tocilizumab) combined or
not with daily subcutaneous injections of anakinra until 28 days or hospital discharge,
whichever is first. During the treatment period, daily clinical assesments of severity, daily
laboratory check-up, measurements of oxygen saturation (pulse oximetry) in relation to FiO2,
regular arterial blood gas measurements, regular chest X-rays, chest CT scans on indication
will be performed.
Other: Usual Care
Usual Care
Drug: Anakinra
Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first
Other Name: KINERET®
Drug: Siltuximab
Siltuximab will be given via single IV infusion at a dose of 11 mg/kg
Other Name: SYLVANT®
Drug: Tocilizumab
Tocilizumab will be given via single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection
Other Name: ROACTEMRA®
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.
AZ Sint-Jan Brugge
Brugge, Belgium
University Hospital Saint-Pierre
Brussels, Belgium
Erasmus University Hospital
Brussels, Belgium
University Hospital Saint-Luc
Brussels, Belgium
University Hospital Antwerp
Edegem, Belgium
Ziekenhuis Oost-Limurg
Genk, Belgium
AZ Sint-Lucas
Gent, Belgium
University Hospital Ghent
Gent, Belgium
Jessa ZH
Hasselt, Belgium
University Hospital Brussels
Jette, Belgium
CHU Tivoli
La Louvière, Belgium
CHR de la Citadelle
Liège, Belgium
University Hospital Liège
Liège, Belgium
Cliniques Saint-Pierre Ottignies
Ottignies-Louvain-la-Neuve, Belgium
AZ Delta
Roeselare, Belgium
Bart Lambrecht, MD, PhD, Principal Investigator
University Hospital, Ghent