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Zilucoplan® in Improving Oxygenation and Short- and Long-term Outcome of COVID-19 Patients With Acute Hypoxic Respiratory Failure (ZILU-COV)

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ClinicalTrials.gov Identifier: NCT04382755
Recruitment Status : Recruiting
First Posted : May 11, 2020
Last Update Posted : July 9, 2020
Sponsor:
Collaborator:
UCB Pharma
Information provided by (Responsible Party):
Bart N. Lambrecht, University Hospital, Ghent

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.


Condition or disease Intervention/treatment Phase
COVID-19 Drug: Zilucoplan® Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Long-term Outcome of COVID-19 Patients With Acute Hypoxic Respiratory Failure
Actual Study Start Date : May 22, 2020
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : September 2021


Arm Intervention/treatment
Active Comparator: Group A (active)
Standard of Care (SoC) + subcutaneous Zilucoplan® + prophylactic antibiotics until 14 days after last Zilucoplan®
Drug: Zilucoplan®
14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan®

Placebo Comparator: Group B (control)
Standard of Care (SoC) + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)
Drug: Placebo
standard of care treatment + 1 week of prophylactic antibiotics + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)




Primary Outcome Measures :
  1. Mean change in oxygenation [ Time Frame: at predose, day 6 and day 15 (or at discharge, whichever comes first) ]
    defined by Pa02/FiO2 ratio while breathing room air, P(Aa)O2 gradient and a/A pO2 ratio

  2. Median change in oxygenation [ Time Frame: at predose, day 6 and day 15 (or at discharge, whichever comes first) ]
    defined by Pa02/FiO2 ratio while breathing room air, P(Aa)O2 gradient and a/A pO2 ratio


Secondary Outcome Measures :
  1. number of AE's (Adverse Events) [ Time Frame: during hospital admission (up to 28 days) ]
  2. number of SAE's (Serious Adverse Events) [ Time Frame: during hospital admission (up to 28 days)] ]
  3. mean change in 6-point ordinal scale change [ Time Frame: between day 1 and respectively day 6, day 15 (or discharge, whichever comes first) and day 28 (by phone call). ]

    6-point ordinal scale defined as

    1. Death
    2. Hospitalized, on invasive mechanical ventilation or ECMO;
    3. Hospitalized, on non-invasive ventilation
    4. Hospitalized, requiring supplemental oxygen
    5. Hospitalized, not requiring supplemental oxygen
    6. Not hospitalized

  4. Time since randomization until improvement in oxygenation [ Time Frame: during hospital admission (up to 28 days) ]
    defined as independence from supplemental oxygen

  5. Number of days with hypoxia [ Time Frame: during hospital admission (up to 28 days) ]
    defined as SpO2 < 93% breathing room air or the dependence on supplemental oxygen

  6. Number of days of supplemental oxygen use [ Time Frame: during hospital admission (up to 28 days) ]
  7. 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) ]
  8. Number of days with fever [ Time Frame: during hospital admission (up to 28 days) ]
    defined as 37.1°C or more

  9. Mean change in CRP levels between day 1 and day 6 [ Time Frame: day 1, day 6 ]
  10. Mean change in CRP levels between day 1 and day 15 (or discharge whichever comes first) [ Time Frame: day 1, day 15 ]
  11. Mean change in ferritin levels between day 1 and day 6 [ Time Frame: day 1, day 6 ]
  12. Mean change in ferritin levels between day 1 and day 15 (or discharge, whichever comes first) [ Time Frame: day 1, day 15 ]
  13. Incidence of AE's [ Time Frame: during hospital admission (up to 28 days) ]
  14. Incidence of SAE's [ Time Frame: at 10-20 weeks follow-up ]
  15. Incidence of SUSAR's (Suspected Unexpected Serious Adverse Reaction) [ Time Frame: during hospital admission (up to 28 days) ]
  16. Incidence of SAR's (Serious Adverse Reaction) [ Time Frame: during hospital admission (up to 28 days) ]
  17. Duration of hospital stay [ Time Frame: during hospital admission (up to 28 days) ]
  18. Duration of hospital stay in survivors [ Time Frame: during hospital admission (up to 28 days) ]
  19. Mean change of SOFA score between day 1 and day 6 (or on discharge, whichever is first) [ Time Frame: day 1, day 6 or on discharge, whichever is first ]
    SOFA score: 0 (best) - 24 (worse)

  20. Mean change of SOFA score between day 1 and day 15 or on discharge, whichever is first) [ Time Frame: day 1, day 15 or on discharge, whichever is first ]
    SOFA score: 0 (best) - 24 (worse)

  21. Percentage of patients reporting each severity rating on a 6-point ordinal scale at randomization, day 6 and 15 (or discharge, whichever comes first) and day 28 (phone call) [ Time Frame: day 1, day 6, day 15 (or discharge, whichever comes first) ]

    6-point ordinal scale:

    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

  22. 6-point Ordinal Scale at 6 and 15 days (or discharge whichever comes first) and day 28 (phone call), in relation to serum D-dimers and complement C5a levels at randomization [ Time Frame: day 1, day 6, day 15 (or discharge, whichever comes first) ]

    6-point ordinal scale:

    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

  23. Incidence of nosocomial bacterial or invasive fungal infection for 28 days (phone call) after enrolment in trial [ Time Frame: day 28 ]
  24. Time since randomization until first use of high-flow oxygen devices in non-ventilated patients [ Time Frame: during hospital admission (up to 28 days) ]
  25. Time since randomization until first use of non-invasive mechanical ventilation in non-ventilated patients [ Time Frame: during hospital admission (up to 28 days) ]
  26. Time since randomization until first use of invasive mechanical ventilation in non-ventilated patients [ Time Frame: during hospital admission (up to 28 days) ]
  27. Number of ventilator-free days [ Time Frame: day 1, day 28 or discharge whichever comes first ]
  28. Duration of invasive and non-invasive mechanical ventilation in ventilated patients [ Time Frame: during hospital admission (up to 28 days) ]
  29. Duration of ICU stay in patients that enrolled in trial on invasive or non-invasive mechanical ventilation for less than 24h prior to or after randomization [ Time Frame: during hospital admission (up to 28 days) ]
  30. Time since randomization to progression to ARDS (Acute Respiratory Distress Syndrome) [ Time Frame: during hospital admission (up to 28 days) ]

    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

  31. Time to progression to ARDS in ventilated patients according to D-dimers at randomization [ Time Frame: during hospital admission (up to 28 days) ]
  32. Time to progression to ARDS in ventilated patients according to complement C5a at randomization [ Time Frame: during hospital admission (up to 28 days) ]
  33. All-cause mortality rate (excluding group that entered during ventilation) [ Time Frame: at day 28 ]
  34. All-cause mortality rate (including group that entered during ventilation) [ Time Frame: at day 28 ]
  35. Percentage of patients in clinical status on 6-point Ordinal Scale [ Time Frame: at 12-22 weeks follow-up ]
  36. Incidence of lung function abnormalities at follow up [ Time Frame: at 12-22 weeks follow-up ]
  37. Incidence of lung fibrosis on chest CT scan at follow up [ Time Frame: at 12-22 weeks follow-up ]
  38. All cause mortality for the entire study population [ Time Frame: at follow up 12-22 weeks ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
    • Patient on ECMO 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
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04382755


Contacts
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Contact: Anja Delporte 003293320228 anja.delporte@uzgent.be
Contact: Bart Lambrecht, MDPhD bart.lambrecht@ugent.be

Locations
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Belgium
OLVZ Aalst Recruiting
Aalst, Belgium, 9300
Contact: Nikolaas De Neve, MD       nikolaas.deneve@olvz-aalst.be   
AZ Sint Jan Brugge Recruiting
Brugge, Belgium, 8000
Contact: Stefaan Vandecasteele, MD Phd    +32-50 45 23 10    stefaan.vandecasteele@azsintjan.be   
Erasmus University Hospital Recruiting
Brussels, Belgium, 1070
Contact: Maya Hites, MD PhD       maya.christina.hites@ulb.ac.be   
AZ Sint-Lucas Recruiting
Gent, Belgium, 9000
Contact: Elke Govaerts, MD       elke.govaerts@azstlucas.be   
University Hospital Ghent Recruiting
Gent, Belgium, 9000
Contact: Anja Delporte    +32-9-3320228    anja.delporte@uzgent.be   
Contact: Bart Lambrecht, MD PhD    +32-9-3329110    bart.lambrecht@ugent.be   
Jan Yperman Ziekenhuis Ieper Recruiting
Ieper, Belgium, 128900
Contact: Wim MD Terryn       wim.terryn@yperman.net   
University Hospital Liège Recruiting
Liège, Belgium, 4000
Contact: Olivier Malaise, MD PhD       olivier.malaise@chuliege.be   
AZ Delta Recruiting
Roeselare, Belgium, 8800
Contact: Ingel Demedts, MD       ingel.demedts@azdelta.be   
AZ Vesalius Recruiting
Tongeren, Belgium, 3700
Contact: Karolien Vanhove, MD       karolien.vanhove@azvesalius.be   
Sponsors and Collaborators
University Hospital, Ghent
UCB Pharma
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Bart N. Lambrecht, Professor in Pulmonology, Director VIB-Inflammational Research Center, University Hospital, Ghent
ClinicalTrials.gov Identifier: NCT04382755    
Other Study ID Numbers: ZILU-COV
First Posted: May 11, 2020    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Bart N. Lambrecht, University Hospital, Ghent:
Acute Lung Injury
Hypoxia
Corona virus
COVID-19
SARS (Severe Acute Respiratory Syndrome)
Acute Respiratory Distress Syndrome
ARDS
Additional relevant MeSH terms:
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Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases