Treatment of COVID-19 Patients With Anti-interleukin Drugs

NCT ID: NCT04330638

Last Updated: 2023-03-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 342 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-04-03
• Study Completion Date: 2021-05-21

Brief Summary

The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6 and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome

Detailed Description

There are currently no treatments directed at halting the cytokine storm and acute lung injury to stop the progression from manageable hypoxia to frank respiratory failure and ARDS in patients with COVID-19 infection. Preventing progression from early acute hypoxia and cytokine release syndrome to frank hypoxic respiratory failure and ARDS could have a huge impact on the foreseeable overflow of the ICU units. In ventilated patients, preventing the onset of ARDS, or shortening ICU stay could also be crucial in this regard.

The clinical status after 15 days treatment is evaluated to measure the effectiveness of tocilizumab, tocilizumab and anakinra, siltuximab, siltuximab and anakinra and anakinra on restoring lung homeostasis,using single IV injection (siltuximab or tocilizumab) combined or not with daily subcutaneous injections of anakinra until 28 days or hospital discharge, whichever is first. During the treatment period, daily clinical assesments of severity, daily laboratory check-up, measurements of oxygen saturation (pulse oximetry) in relation to FiO2, regular arterial blood gas measurements, regular chest X-rays, chest CT scans on indication will be performed.

Conditions

COVID-19

Study Design

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

Study Groups

Usual Care

Group Type: PLACEBO_COMPARATOR

Usual Care

Intervention Type: OTHER

Usual Care

Anakinra

Group Type: ACTIVE_COMPARATOR

Anakinra

Intervention Type: DRUG

Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first

Siltuximab

Group Type: ACTIVE_COMPARATOR

Siltuximab

Intervention Type: DRUG

Siltuximab will be given via single IV infusion at a dose of 11 mg/kg

Anakinra + Siltuximab

Group Type: ACTIVE_COMPARATOR

Anakinra

Intervention Type: DRUG

Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first

Siltuximab

Intervention Type: DRUG

Siltuximab will be given via single IV infusion at a dose of 11 mg/kg

Tocilizumab

Group Type: ACTIVE_COMPARATOR

Tocilizumab

Intervention Type: DRUG

Tocilizumab will be given via single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection

Anakinra + Tocilizumab

Group Type: ACTIVE_COMPARATOR

Anakinra

Intervention Type: DRUG

Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first

Tocilizumab

Intervention Type: DRUG

Tocilizumab will be given via single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection

Interventions

Usual Care

Usual Care

Intervention Type: OTHER

Anakinra

Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first

Intervention Type: DRUG

Siltuximab

Siltuximab will be given via single IV infusion at a dose of 11 mg/kg

Intervention Type: DRUG

Tocilizumab

Tocilizumab will be given via single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection

Intervention Type: DRUG

Other Intervention Names

KINERET®; SYLVANT®; ROACTEMRA®

Eligibility Criteria

Inclusion Criteria

• Recent ( ≥ 6 days of flu-like symptoms or malaise yet ≤16 days of flu-like symptoms or malaise prior to randomization) infection with COVID-19.
• Confident 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.
• 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 COVID-19 infected. In all cases, this needs confirmation by later seroconversion.
• Presence of hypoxia defined as PaO2/FiO2 below 350 while breathing room air in upright position or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation
• signs of cytokine release syndrome defined as ANY of the following:

1. serum ferritin concentration >1000 mcg/L and rising since last 24h

2. single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen device or mechanical ventilation

3. 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 last 24h
• D-Dimers > 1000 ng/mL and rising since last 24h
• CRP above 70mg/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
• Chest X-ray or CT scan showing bilateral infiltrates within last 2 days
• Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients
• Age ≥ 18yrs
• Male or Female
• 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 any of the study medications, or any component of the product.
• mechanical ventilation > 24 h at Randomization
• Patient on ECMO at time of screening
• clinical frailty scale above 3 (This frailty score is the patient status before first symptoms of 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 (> 20 mg methylprednisolone or equivalent) for COVID-19 unrelated disorder
• patients on immunosuppressant or immunomodulatory drugs
• patients on current anti-IL1 or anti-IL6 treatment
• signs of active tuberculosis
• serum transaminase levels >5 times upper limit of normal
• bowel perforation or diverticulitis
• pregnant or breastfeeding females (all female subjects deemed of childbearing potential by the investigator must have negative pregnancy test at screening)
• Women of childbearing potential must have a negative serum pregnancy test pre-dose on day 1. Woùmen of childbearing potential must consistently and correctly use (during the entire treatment period and 3 months after last reatment) 1 highly effective method for contraception.

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

Sponsors

Belgium Health Care Knowledge Centre

OTHER_GOV

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 Lambrecht, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Ghent

Locations

AZ Sint-Jan Brugge

Bruges, , Belgium

University Hospital Saint-Pierre

Brussels, , Belgium

Erasmus University Hospital

Brussels, , Belgium

University Hospital Saint-Luc

Brussels, , Belgium

University Hospital Antwerp

Edegem, , Belgium

Ziekenhuis Oost-Limurg

Genk, , Belgium

AZ Sint-Lucas

Ghent, , Belgium

University Hospital Ghent

Ghent, , Belgium

Jessa ZH

Hasselt, , Belgium

University Hospital Brussels

Jette, , Belgium

CHU Tivoli

La Louvière, , Belgium

CHR de la Citadelle

Liège, , Belgium

University Hospital Liège

Liège, , Belgium

Cliniques Saint-Pierre Ottignies

Ottignies-Louvain-la-Neuve, , Belgium

AZ Delta

Roeselare, , Belgium

Countries

Belgium

References

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Reference Type: DERIVED

PMID: 35080773 (View on PubMed)

Declercq J, Van Damme KFA, De Leeuw E, Maes B, Bosteels C, Tavernier SJ, De Buyser S, Colman R, Hites M, Verschelden G, Fivez T, Moerman F, Demedts IK, Dauby N, De Schryver N, Govaerts E, Vandecasteele SJ, Van Laethem J, Anguille S, van der Hilst J, Misset B, Slabbynck H, Wittebole X, Lienart F, Legrand C, Buyse M, Stevens D, Bauters F, Seys LJM, Aegerter H, Smole U, Bosteels V, Hoste L, Naesens L, Haerynck F, Vandekerckhove L, Depuydt P, van Braeckel E, Rottey S, Peene I, Van Der Straeten C, Hulstaert F, Lambrecht BN. Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial. Lancet Respir Med. 2021 Dec;9(12):1427-1438. doi: 10.1016/S2213-2600(21)00377-5. Epub 2021 Oct 29.

Reference Type: DERIVED

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Reference Type: DERIVED

PMID: 33935163 (View on PubMed)

Maes B, Bosteels C, De Leeuw E, Declercq J, Van Damme K, Delporte A, Demeyere B, Vermeersch S, Vuylsteke M, Willaert J, Bolle L, Vanbiervliet Y, Decuypere J, Libeer F, Vandecasteele S, Peene I, Lambrecht B. Treatment of severely ill COVID-19 patients with anti-interleukin drugs (COV-AID): A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Jun 3;21(1):468. doi: 10.1186/s13063-020-04453-5.

Reference Type: DERIVED

PMID: 32493441 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

COV-AID

Identifier Type: -

Identifier Source: org_study_id