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

NCT04382755 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: ZILU-COV
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 9

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.

Conditions

COVID-19

Keywords

Acute Lung Injury; Hypoxia; Corona virus; COVID-19; SARS (Severe Acute Respiratory Syndrome); Acute Respiratory Distress Syndrome; ARDS

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (25)

• Mean Change in 6-point Ordinal Scale Change for Clinical Improvement

  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

  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

  during hospital admission (up to 28 days)

Other Outcomes (4)

• Number of Ventilator-free Days

  day 1, day 28 or discharge whichever comes first

• Time Since Randomization to Progression to ARDS (Acute Respiratory Distress Syndrome)

  during hospital admission (up to 28 days)

• Number of Participants With Lung Fibrosis on Chest CT Scan at Follow up

  at 12-22 weeks follow-up

Study Arms (2)

Group A (active)

ACTIVE COMPARATOR

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

Drug: Zilucoplan®

Group B (control)

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Zilucoplan® DRUG

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

Group A (active)

Placebo DRUG

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

Group B (control)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• University Hospital, Ghent: lead
• UCB Pharma: collaborator

Study Sites (9)

OLVZ Aalst

Aalst, 9300, Belgium

Location

AZ Sint Jan Brugge

Bruges, 8000, Belgium

Location

Erasmus University Hospital

Brussels, 1070, Belgium

Location

AZ Sint-Lucas

Ghent, 9000, Belgium

Location

University Hospital Ghent

Ghent, 9000, Belgium

Location

Jan Yperman Ziekenhuis Ieper

Ieper, 128900, Belgium

Location

University Hospital Liège

Liège, 4000, Belgium

Location

AZ Delta

Roeselare, 8800, Belgium

Location

AZ Vesalius

Tongeren, 3700, Belgium

Location

Related Publications (2)

• 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.

  PMID: 35945604 DERIVED

• 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.

  PMID: 33213529 DERIVED

MeSH Terms

Conditions

COVID-19; Acute Lung Injury; Hypoxia; Severe Acute Respiratory Syndrome; Respiratory Distress Syndrome

Interventions

zilucoplan

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Lung Injury; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Respiration Disorders

Results Point of Contact

• Title: Anja Delporte
• Organization: UZ Gent

anja.delporte@uzgent.be

+3293320228

Study Officials

• Bart N Lambrecht, MDPhD

  University Ghent

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor in Pulmonology, Director VIB-Inflammational Research Center

Study Record Dates

• First Submitted: May 7, 2020
• First Posted: May 11, 2020
• Study Start: May 22, 2020
• Primary Completion: December 29, 2020
• Study Completion: April 9, 2021
• Last Updated: September 14, 2023
• Results First Posted: September 14, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

BE (9)