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

NCT ID: NCT04382755

Last Updated: 2023-09-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 81 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-22
• Study Completion Date: 2021-04-09

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.

Conditions

COVID-19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group A (active)

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

Group Type: ACTIVE_COMPARATOR

Zilucoplan®

Intervention Type: DRUG

14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan®

Group B (control)

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

standard of care treatment + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)

Interventions

Zilucoplan®

14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan®

Intervention Type: DRUG

Placebo

standard of care treatment + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)

Intervention Type: DRUG

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

UCB Pharma

INDUSTRY

Sponsor Role: collaborator

University Hospital, Ghent

OTHER

Sponsor Role: lead

Responsible Party

Bart N. Lambrecht

Professor in Pulmonology, Director VIB-Inflammational Research Center

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bart N Lambrecht, MDPhD

Role: PRINCIPAL_INVESTIGATOR

University Ghent

Locations

OLVZ Aalst

Aalst, , Belgium

AZ Sint Jan Brugge

Bruges, , Belgium

Erasmus University Hospital

Brussels, , Belgium

AZ Sint-Lucas

Ghent, , Belgium

University Hospital Ghent

Ghent, , Belgium

Jan Yperman Ziekenhuis Ieper

Ieper, , Belgium

University Hospital Liège

Liège, , Belgium

AZ Delta

Roeselare, , Belgium

AZ Vesalius

Tongeren, , Belgium

Countries

Belgium

References

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.

Reference Type: DERIVED

PMID: 35945604 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33213529 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

ZILU-COV

Identifier Type: -

Identifier Source: org_study_id