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Zilucoplan® in Improving Oxygenation, Short-, Longterm Outcome of COVID19 Patients With Acute Hypoxic Respiratory Failure (ZILU-COV)

Primary Purpose

COVID-19

Status
Completed
Phase
Phase 2
Locations
Belgium
Study Type
Interventional
Intervention
Zilucoplan®
Placebo
Sponsored by
University Hospital, Ghent
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 focused on measuring Acute Lung Injury, Hypoxia, Corona virus, COVID-19, SARS (Severe Acute Respiratory Syndrome), Acute Respiratory Distress Syndrome, ARDS

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • OLVZ Aalst
  • AZ Sint Jan Brugge
  • Erasmus University Hospital
  • AZ Sint-Lucas
  • University Hospital Ghent
  • Jan Yperman Ziekenhuis Ieper
  • University Hospital Liège
  • AZ Delta
  • AZ Vesalius

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Group A (active)

Group B (control)

Arm Description

Standard of Care (SoC) + subcutaneous Zilucoplan® + prophylactic antibiotics until 14 days after last Zilucoplan®

Standard of Care (SoC) + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)

Outcomes

Primary Outcome Measures

Change in Oxygenation
defined by Pa02/FiO2 ratio while breathing room air, P(Aa)O2 gradient and a/A pO2 ratio

Secondary Outcome Measures

Mean Change in 6-point Ordinal Scale Change for Clinical Improvement
6-point ordinal scale defined as Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized
Number of Days With Hypoxia
defined as SpO2 < 93% breathing room air or the dependence on supplemental oxygen
Number of Days of Supplemental Oxygen Use
Time to Absence of Fever (Defined as 37.1°C or More) for More Than 48h Without Antipyretic
Number of Days With Fever
defined as 37.1°C or more
Mean Change in CRP Levels Between Day 1 and Day 6
Mean Change in CRP Levels Between Day 1 and Day 15 (or Discharge Whichever Comes First)
Mean Change in Ferritin Levels Between Day 1 and Day 6
Mean Change in Ferritin Levels Between Day 1 and Day 15 (or Discharge, Whichever Comes First)
Number of Participants With Adverse Events
Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Number of Participants With Serious Adverse Events
A serious adverse event is any untoward medical occurrence that: results in death is life-threatening requires inpatient hospitalisation or prolongation of existing hospitalisation results in persistent or significant disability/incapacity consists of a congenital anomaly or birth defect Other 'important medical events' may also be considered serious if they jeopardise the subject or require an intervention to prevent one of the above consequences. NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.
Number of Participants With SUSAR's (Suspected Unexpected Serious Adverse Reaction)
A serious adverse reaction, the nature and severity of which is not consistent with the information about the medicinal product in question set out: in the case of a product with a marketing authorisation, in the summary of product characteristics (SmPC) for that product in the case of any other investigational medicinal product, in the investigator's brochure (IB) relating to the study in question
Number of Participants With SAR's (Serious Adverse Reaction)
An adverse event that is both serious and, in the opinion of the reporting Investigator, believed with reasonable probability to be due to one of the study treatments, based on the information provided.
Duration of Hospital Stay
Duration of Hospital Stay in Survivors
Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First)
The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points.
Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First)
The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points.
Number of Participants With Nosocomial Bacterial or Invasive Fungal Infection for 28 Days (Phone Call) After Enrollment in Trial
Median Time to at Least a 2-point Improvement on the 6-point Ordinal Scale or Discharge During the 28-day Assessment Period (Range) - Days
The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome
Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement
The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome
Number of Participants in Each Category of the WHO Performance Scale
The WHO performance status classification categorises patients as: 0: able to carry out all normal activity without restriction restricted in strenuous activity but ambulatory and able to carry out light work ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours symptomatic and in a chair or in bed for greater than 50% of the day but not bedridden completely disabled; cannot carry out any self-care; totally confined to bed or chair.
Result of 6 Minute Walk Test
Distance in 6 minute walk test. The 6 Minute Walk Test is a sub-maximal exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. Total distance in meters. A higher score has a better outcome
All-cause Mortality Rate (Excluding Group That Entered During Ventilation)
All-cause Mortality Rate (Including Group That Entered During Ventilation)
All Cause Mortality for the Entire Study Population

Full Information

First Posted
May 7, 2020
Last Updated
September 1, 2023
Sponsor
University Hospital, Ghent
Collaborators
UCB Pharma
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1. Study Identification

Unique Protocol Identification Number
NCT04382755
Brief Title
Zilucoplan® in Improving Oxygenation, Short-, Longterm Outcome of COVID19 Patients With Acute Hypoxic Respiratory Failure
Acronym
ZILU-COV
Official Title
A Prospective Randomized Open-label Interventional Study to Investigate the Efficacy of Complement C5 Inhibition With Zilucoplan® in Improving Oxygenation and Short-and Longterm Outcome of COVID19 Patients With Acute Hypoxic Respiratory Failure
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
May 22, 2020 (Actual)
Primary Completion Date
December 29, 2020 (Actual)
Study Completion Date
April 9, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital, Ghent
Collaborators
UCB Pharma

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed Description
This investigator-initiated trial is a phase 2 academic, prospective, 2:1 randomized, open-label, multicenter interventional study designed to investigate the efficacy of subcutaneous Zilucoplan® in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. The hypothesis of the proposed intervention is that Zilucoplan® has profound effects on inhibiting acute lung injury induced by 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. We will randomize patients with confirmed COVID19 with acute hypoxic respiratory failure (O2 saturation below 93% on minimal 2l/min O2 therapy; and/or PaO2/FiO2 below 350 mmHg) to receive up to 14 days of SC Zilucoplan® on top of standard of care (active group A), or to receive standard of care treatment (control group B). Randomization will be done at a 2:1 ratio active: control group. In the active group A, patients will additionally receive daily antibiotics (daily 3rd generation cephalosporin IV while in hospital, followed by oral ciprofloxacin while discharged) as primary prophylaxis against meningococcal disease until 14 days after the last dose of Zilucoplan®. Control group B will receive standard of care and prophylactic antibiotics (3rd generation cephalosporin IV) for only 1 week (or until hospital discharge whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. In case of allergies to these antibiotics, or on clinical indication, these antibiotics may be switched to antibiotics that also cover Neisseria meningitidis. To measure the effectiveness of Zilucoplan® on restoring lung homeostasis, the primary endpoint of this intervention is measuring change in oxygenation parameters comparing baseline values (pretreatment) to values predose day 6 and to values at day 15 (or discharge whichever comes first) post-randomizationin group A and group B and the differences in these values between group A and group B.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19
Keywords
Acute Lung Injury, Hypoxia, Corona virus, COVID-19, SARS (Severe Acute Respiratory Syndrome), Acute Respiratory Distress Syndrome, ARDS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
81 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group A (active)
Arm Type
Active Comparator
Arm Description
Standard of Care (SoC) + subcutaneous Zilucoplan® + prophylactic antibiotics until 14 days after last Zilucoplan®
Arm Title
Group B (control)
Arm Type
Placebo Comparator
Arm Description
Standard of Care (SoC) + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)
Intervention Type
Drug
Intervention Name(s)
Zilucoplan®
Intervention Description
14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan®
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
standard of care treatment + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)
Primary Outcome Measure Information:
Title
Change in Oxygenation
Description
defined by Pa02/FiO2 ratio while breathing room air, P(Aa)O2 gradient and a/A pO2 ratio
Time Frame
at predose, day 6 and day 15 (or at discharge, whichever comes first)
Secondary Outcome Measure Information:
Title
Mean Change in 6-point Ordinal Scale Change for Clinical Improvement
Description
6-point ordinal scale defined as Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized
Time Frame
between day 1 and respectively day 6, day 15 (or discharge, whichever comes first) and day 28 (by phone call).
Title
Number of Days With Hypoxia
Description
defined as SpO2 < 93% breathing room air or the dependence on supplemental oxygen
Time Frame
during hospital admission (up to 28 days)
Title
Number of Days of Supplemental Oxygen Use
Time Frame
during hospital admission (up to 28 days)
Title
Time to Absence of Fever (Defined as 37.1°C or More) for More Than 48h Without Antipyretic
Time Frame
during hospital admission (up to 28 days)
Title
Number of Days With Fever
Description
defined as 37.1°C or more
Time Frame
during hospital admission (up to 28 days)
Title
Mean Change in CRP Levels Between Day 1 and Day 6
Time Frame
day 1, day 6
Title
Mean Change in CRP Levels Between Day 1 and Day 15 (or Discharge Whichever Comes First)
Time Frame
day 1, day 15
Title
Mean Change in Ferritin Levels Between Day 1 and Day 6
Time Frame
day 1, day 6
Title
Mean Change in Ferritin Levels Between Day 1 and Day 15 (or Discharge, Whichever Comes First)
Time Frame
day 1, day 15
Title
Number of Participants With Adverse Events
Description
Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time Frame
during hospital admission (up to 28 days)
Title
Number of Participants With Serious Adverse Events
Description
A serious adverse event is any untoward medical occurrence that: results in death is life-threatening requires inpatient hospitalisation or prolongation of existing hospitalisation results in persistent or significant disability/incapacity consists of a congenital anomaly or birth defect Other 'important medical events' may also be considered serious if they jeopardise the subject or require an intervention to prevent one of the above consequences. NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.
Time Frame
at 10-20 weeks follow-up
Title
Number of Participants With SUSAR's (Suspected Unexpected Serious Adverse Reaction)
Description
A serious adverse reaction, the nature and severity of which is not consistent with the information about the medicinal product in question set out: in the case of a product with a marketing authorisation, in the summary of product characteristics (SmPC) for that product in the case of any other investigational medicinal product, in the investigator's brochure (IB) relating to the study in question
Time Frame
during hospital admission (up to 28 days)
Title
Number of Participants With SAR's (Serious Adverse Reaction)
Description
An adverse event that is both serious and, in the opinion of the reporting Investigator, believed with reasonable probability to be due to one of the study treatments, based on the information provided.
Time Frame
during hospital admission (up to 28 days)
Title
Duration of Hospital Stay
Time Frame
at 12-22 weeks follow-up
Title
Duration of Hospital Stay in Survivors
Time Frame
at 12-22 weeks follow-up
Title
Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First)
Description
The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points.
Time Frame
day 1, day 6 or on discharge, whichever is first
Title
Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First)
Description
The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points.
Time Frame
day 1, day 15 or on discharge, whichever is first
Title
Number of Participants With Nosocomial Bacterial or Invasive Fungal Infection for 28 Days (Phone Call) After Enrollment in Trial
Time Frame
day 28
Title
Median Time to at Least a 2-point Improvement on the 6-point Ordinal Scale or Discharge During the 28-day Assessment Period (Range) - Days
Description
The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome
Time Frame
Day 28
Title
Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement
Description
The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome
Time Frame
at 12-22 weeks follow-up
Title
Number of Participants in Each Category of the WHO Performance Scale
Description
The WHO performance status classification categorises patients as: 0: able to carry out all normal activity without restriction restricted in strenuous activity but ambulatory and able to carry out light work ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours symptomatic and in a chair or in bed for greater than 50% of the day but not bedridden completely disabled; cannot carry out any self-care; totally confined to bed or chair.
Time Frame
during hospital admission (up to 28 days)
Title
Result of 6 Minute Walk Test
Description
Distance in 6 minute walk test. The 6 Minute Walk Test is a sub-maximal exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. Total distance in meters. A higher score has a better outcome
Time Frame
at 12-22 weeks follow-up
Title
All-cause Mortality Rate (Excluding Group That Entered During Ventilation)
Time Frame
at day 28
Title
All-cause Mortality Rate (Including Group That Entered During Ventilation)
Time Frame
at day 28
Title
All Cause Mortality for the Entire Study Population
Time Frame
at follow up 12-22 weeks
Other Pre-specified Outcome Measures:
Title
Number of Ventilator-free Days
Time Frame
day 1, day 28 or discharge whichever comes first
Title
Time Since Randomization to Progression to ARDS (Acute Respiratory Distress Syndrome)
Description
criteria-defined ARDS criteria-defined ARDS according to the adapted Berlin criteria as follow: within 1 week of a known Clinical insult or new or worsening respiratory symptoms bilateral infiltrates not supposed to be of cardiac origin or fluid overload PaO2/FiO2 < 300 mmHg
Time Frame
during hospital admission (up to 28 days)
Title
Number of Participants With Lung Fibrosis on Chest CT Scan at Follow up
Time Frame
at 12-22 weeks follow-up
Title
Time Since Randomization Until Improvement in Oxygenation
Description
defined as independence from supplemental oxygen
Time Frame
during hospital admission (up to 28 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bart N Lambrecht, MDPhD
Organizational Affiliation
University Ghent
Official's Role
Principal Investigator
Facility Information:
Facility Name
OLVZ Aalst
City
Aalst
ZIP/Postal Code
9300
Country
Belgium
Facility Name
AZ Sint Jan Brugge
City
Brugge
ZIP/Postal Code
8000
Country
Belgium
Facility Name
Erasmus University Hospital
City
Brussels
ZIP/Postal Code
1070
Country
Belgium
Facility Name
AZ Sint-Lucas
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
University Hospital Ghent
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
Jan Yperman Ziekenhuis Ieper
City
Ieper
ZIP/Postal Code
128900
Country
Belgium
Facility Name
University Hospital Liège
City
Liège
ZIP/Postal Code
4000
Country
Belgium
Facility Name
AZ Delta
City
Roeselare
ZIP/Postal Code
8800
Country
Belgium
Facility Name
AZ Vesalius
City
Tongeren
ZIP/Postal Code
3700
Country
Belgium

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35945604
Citation
De Leeuw E, Van Damme KFA, Declercq J, Bosteels C, Maes B, Tavernier SJ, Detalle L, Smart T, Glatt S, Debeuf N, Deckers J, Lameire S, Vandecasteele SJ, De Neve N, Demedts IK, Govaerts E, Knoop C, Vanhove K, Moutschen M, Terryn W, Depuydt P, Van Braeckel E, Haerynck F, Hendrickx TCJ, Parrein V, Lalla M, Brittain C, Lambrecht BN. Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial. Respir Res. 2022 Aug 9;23(1):202. doi: 10.1186/s12931-022-02126-2.
Results Reference
derived
PubMed Identifier
33213529
Citation
Declercq J, Bosteels C, Van Damme K, De Leeuw E, Maes B, Vandecauter A, Vermeersch S, Delporte A, Demeyere B, Vuylsteke M, Lalla M, Smart T, Detalle L, Bouw R, Streffer J, Degeeter T, Vergotte M, Guisez T, Van Braeckel E, Van Der Straeten C, Lambrecht BN. Zilucoplan in patients with acute hypoxic respiratory failure due to COVID-19 (ZILU-COV): A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Nov 19;21(1):934. doi: 10.1186/s13063-020-04884-0.
Results Reference
derived

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Zilucoplan® in Improving Oxygenation, Short-, Longterm Outcome of COVID19 Patients With Acute Hypoxic Respiratory Failure

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