The study is a randomized controlled, open-label trial comparing subcutaneous Zilucoplan® with standard of care to standard of care alone. In the active group, Zilucoplan® will be administered subcutaneously once daily for 14 days or till discharge from the hospital, whichever comes first. The hypothesis of the proposed intervention is that Zilucoplan® (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. This hypothesis is based on experiments performed in mice showing that C5a blockade can prevent mortality and prevent ARDS in mice with post-viral acute lung injury. Eligible patients include patients with confirmed COVID-19 infection suffering from hypoxic respiratory failure defined as O2 saturation below 93% on minimal 2l/min O2 therapy and/or ratio PaO2/FiO2 below 350.
Drug: Zilucoplan®
14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan®
Drug: Placebo
standard of care treatment + 1 week of prophylactic antibiotics + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)
Inclusion Criteria:
- Recent (≥6 days and ≤16 days of flu-like symptoms or malaise prior to randomization)
infection with COVID-19.
- 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. For patients with a negative SARS-CoV-2 PCR and either a positive
SARS-CoV-2 antigen or antibody test, the presence of suggestive lesions for COVID-19
on chest-CT scan is mandatory.
- 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 SARS-CoV-2-infected. In all
cases, this needs confirmation by later seroconversion.
- Presence of hypoxia defined as :
- O2 saturation below 93% on minimal 2l/min O2 therapy; and/or
- PaO2/FiO2 below 350 mmHg (Strongly recommended: patient in upright position,
after minimal 3 minutes without supplemental oxygen; In ventilated patients or
ECMO patients PaO2 can be taken from invasive arterial line and FiO2 taken
directly from mechanical ventilation settings).
- Signs of acute lung injury and/or cytokine release syndrome defined as ANY of the
following
- serum ferritin concentration >1000 mcg/L and rising since last 24h
- single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen
device (Optiflow) or non-invasive or invasive mechanical ventilation
- 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 since last 24h
- D-Dimers > 1000 ng/mL and rising since last 24h
- CRP above 70 mg/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
- Low dose Chest CT or HRCT or Angio Chest CT scan showing bilateral infiltrates within
last 2 days prior to randomisation
- Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients
- Age ≥ 18 years
- Women of childbearing potential must have a negative serum pregnancy test pre-dose on
day 1. Women of childbearing potential must consistently and correctly use (during the
entire treatment period and 4weeks after last Zilucoplan® administration ) at least 1
highly effective method for contraception.
- 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
Zilucoplan® or inability to receive antibiotic prophylaxis due to allergy to ALL of
the antibiotics that can be given for prophylaxis of meningococcal disease
- History of active or past meningococcal disease
- Invasive mechanical ventilation > 24 h at randomization
- Patient on ECMO at screening
- Clinical frailty scale above 3 before onset of the COVID-19 episode
- Weight below 54 kg as measured max 1 week prior to inclusion
- Weight above 150 kg as measured max 1 week prior to inclusion
- 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 (> 8 mg methylprednisolone or equivalent for
more than 1 month) or other moderately immunosuppressive drugs (in the opinion of the
investigator) for COVID19 unrelated disorder
- Patients on current complement inhibiting drugs
- Serum transaminase levels >5 times upper limit of normal, unless there are clear signs
of cytokine release syndrome defined by LDH >300 IU/L and ferritin >700 ng/ml
- Pregnant or breastfeeding females (all female subjects deemed of childbearing
potential by the investigator must have negative pregnancy test at screening)
OLVZ Aalst
Aalst, Belgium
AZ Sint Jan Brugge
Brugge, Belgium
Erasmus University Hospital
Brussels, Belgium
AZ Sint-Lucas
Gent, Belgium
University Hospital Ghent
Gent, Belgium
Jan Yperman Ziekenhuis Ieper
Ieper, Belgium
University Hospital Liège
Liège, Belgium
AZ Delta
Roeselare, Belgium
AZ Vesalius
Tongeren, Belgium