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

Sponsor

University Hospital, Ghent (Other)

Overall Status

Completed

CT.gov ID

NCT04382755

Collaborator

UCB Pharma (Industry)

Enrollment

Locations

Arms

10.6

Actual Duration (Months)

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Zilucoplan® Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Actual 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

Actual Primary Completion Date :

Dec 29, 2020

Actual Study Completion Date :

Apr 9, 2021

Arms and Interventions

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)

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)

Outcome Measures

Primary Outcome Measures

Change in oxygenation [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

number of AE's (Adverse Events) [during hospital admission (up to 28 days)]
number of SAE's (Serious Adverse Events) [during hospital admission (up to 28 days)]]
mean change in 6-point ordinal scale change [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 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 since randomization until improvement in oxygenation [during hospital admission (up to 28 days)]
defined as independence from supplemental oxygen
Number of days with hypoxia [during hospital admission (up to 28 days)]
defined as SpO2 < 93% breathing room air or the dependence on supplemental oxygen
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 [during hospital admission (up to 28 days)]
defined as 37.1°C or more
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]
Incidence of AE's [during hospital admission (up to 28 days)]
Incidence of SAE's [at 10-20 weeks follow-up]
Incidence of SUSAR's (Suspected Unexpected Serious Adverse Reaction) [during hospital admission (up to 28 days)]
Incidence of SAR's (Serious Adverse Reaction) [during hospital admission (up to 28 days)]
Duration of hospital stay [during hospital admission (up to 28 days)]
Duration of hospital stay in survivors [during hospital admission (up to 28 days)]
Mean change of SOFA score between day 1 and day 6 (or on discharge, whichever is first) [day 1, day 6 or on discharge, whichever is first]
SOFA score: 0 (best) - 24 (worse)
Mean change of SOFA score between day 1 and day 15 or on discharge, whichever is first) [day 1, day 15 or on discharge, whichever is first]
SOFA score: 0 (best) - 24 (worse)
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) [day 1, day 6, day 15 (or discharge, whichever comes first)]
6-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized
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 [day 1, day 6, day 15 (or discharge, whichever comes first)]
6-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized
Incidence of nosocomial bacterial or invasive fungal infection for 28 days (phone call) after enrolment in trial [day 28]
Time since randomization until first use of high-flow oxygen devices in non-ventilated patients [during hospital admission (up to 28 days)]
Time since randomization until first use of non-invasive mechanical ventilation in non-ventilated patients [during hospital admission (up to 28 days)]
Time since randomization until first use of invasive mechanical ventilation in non-ventilated patients [during hospital admission (up to 28 days)]
Number of ventilator-free days [day 1, day 28 or discharge whichever comes first]
Duration of invasive and non-invasive mechanical ventilation in ventilated patients [during hospital admission (up to 28 days)]
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 [during hospital admission (up to 28 days)]
Time since randomization to progression to ARDS (Acute Respiratory Distress Syndrome) [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
Time to progression to ARDS in ventilated patients according to D-dimers at randomization [during hospital admission (up to 28 days)]
Time to progression to ARDS in ventilated patients according to complement C5a at randomization [during hospital admission (up to 28 days)]
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]
Percentage of patients in clinical status on 6-point Ordinal Scale [at 12-22 weeks follow-up]
Incidence of lung function abnormalities at follow up [at 12-22 weeks follow-up]
Incidence of lung fibrosis on chest CT scan at follow up [at 12-22 weeks follow-up]
All cause mortality for the entire study population [at follow up 12-22 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	OLVZ Aalst	Aalst	Belgium	9300
2	AZ Sint Jan Brugge	Brugge	Belgium	8000
3	Erasmus University Hospital	Brussels	Belgium	1070
4	AZ Sint-Lucas	Gent	Belgium	9000
5	University Hospital Ghent	Gent	Belgium	9000
6	Jan Yperman Ziekenhuis Ieper	Ieper	Belgium	128900
7	University Hospital Liège	Liège	Belgium	4000
8	AZ Delta	Roeselare	Belgium	8800
9	AZ Vesalius	Tongeren	Belgium	3700