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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Zilucoplan®
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A (active)<br>Standard of Care (SoC) + subcutaneous Zilucoplan® + prophylactic antibiotics until 14 days after last Zilucoplan® | Drug: Zilucoplan®<br>* 14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan®<br>|
| Placebo Comparator: Group B (control)<br>Standard of Care (SoC) + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first) | Drug: Placebo<br>* standard of care treatment + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Oxygenation | defined by Pa02/FiO2 ratio while breathing room air, P(Aa)O2 gradient and a/A pO2 ratio | at predose, day 6 and day 15 (or at discharge, whichever comes first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | between day 1 and respectively day 6, day 15 (or discharge, whichever comes first) and day 28 (by phone call). | 
| Number of Days With Hypoxia | defined as SpO2 < 93% breathing room air or the dependence on supplemental oxygen | during hospital admission (up to 28 days) | 
| Number of Days of Supplemental Oxygen Use |  | during hospital admission (up to 28 days) | 
| Time to Absence of Fever (Defined as 37.1°C or More) for More Than 48h Without Antipyretic |  | during hospital admission (up to 28 days) | 
| Number of Days With Fever | defined as 37.1°C or more | during hospital admission (up to 28 days) | 
| Mean Change in CRP Levels Between Day 1 and Day 6 |  | day 1, day 6 | 
| Mean Change in CRP Levels Between Day 1 and Day 15 (or Discharge Whichever Comes First) |  | day 1, day 15 | 
| Mean Change in Ferritin Levels Between Day 1 and Day 6 |  | day 1, day 6 | 
| Mean Change in Ferritin Levels Between Day 1 and Day 15 (or Discharge, Whichever Comes First) |  | day 1, day 15 | 
| 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. | during hospital admission (up to 28 days) | 
| 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. | at 10-20 weeks follow-up | 
| 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 | during hospital admission (up to 28 days) | 
| 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. | during hospital admission (up to 28 days) | 
| Duration of Hospital Stay |  | at 12-22 weeks follow-up | 
| Duration of Hospital Stay in Survivors |  | at 12-22 weeks follow-up | 
| 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. | day 1, day 6 or on discharge, whichever is first | 
| 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. | day 1, day 15 or on discharge, whichever is first | 
| Number of Participants With Nosocomial Bacterial or Invasive Fungal Infection for 28 Days (Phone Call) After Enrollment in Trial |  | day 28 | 
| 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 | Day 28 | 
| 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 | at 12-22 weeks follow-up | 
| 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. | during hospital admission (up to 28 days) | 
| 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 | at 12-22 weeks follow-up | 
| All-cause Mortality Rate (Excluding Group That Entered During Ventilation) |  | at day 28 | 
| All-cause Mortality Rate (Including Group That Entered During Ventilation) |  | at day 28 | 
| All Cause Mortality for the Entire Study Population |  | at follow up 12-22 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lung Injury, Hypoxia, Corona virus, COVID-19, SARS (Severe Acute Respiratory Syndrome), Acute Respiratory Distress Syndrome, ARDS