Zilucoplan® in Improving Oxygenation, Short-, Longterm Outcome of COVID19 Patients With Acute Hypoxic Respiratory Failure
Condition: COVID-19
MeSH terms: COVID-19; Respiratory Insufficiency
Intervention: Zilucoplan®; Placebo
Intervention description: 14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan®; standard of care treatment + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 81.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Lung Injury; Hypoxia; Corona virus; COVID-19; SARS (Severe Acute Respiratory Syndrome); Acute Respiratory Distress Syndrome; ARDS

Summary:

      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.
    

Eligibility criteria:

        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)