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A Prospective, Randomized, Factorial Design, Interventional Study to Compare the Safety and Efficacy of Combinations of Blockade of Interleukin-6 Pathway and Interleukin-1 Pathway to Best Standard of Care in Improving Oxygenation and Short- and Long-term Outcome of COVID-19 Patients With Acute Hypoxic Respiratory Failure and Systemic Cytokine Release Syndrome

Trial Profile

A Prospective, Randomized, Factorial Design, Interventional Study to Compare the Safety and Efficacy of Combinations of Blockade of Interleukin-6 Pathway and Interleukin-1 Pathway to Best Standard of Care in Improving Oxygenation and Short- and Long-term Outcome of COVID-19 Patients With Acute Hypoxic Respiratory Failure and Systemic Cytokine Release Syndrome

Status: Completed
Phase of Trial: Phase III

Latest Information Update: 16 Mar 2023

At a glance

  • Drugs Anakinra (Primary) ; Siltuximab (Primary) ; Tocilizumab (Primary)
  • Indications Acute hypoxia; COVID 2019 infections; Cytokine release syndrome; Respiratory insufficiency; SARS-CoV-2 acute respiratory disease
  • Focus Therapeutic Use
  • Acronyms COV-AID
  • Most Recent Events

    • 15 Jul 2021 Status changed from active, no longer recruiting to completed.
    • 01 Mar 2021 Planned End Date changed from 1 Mar 2021 to 12 Apr 2021.
    • 14 Dec 2020 For Hypoxic-respiratory-failure and respiratory-insufficiency narrower term is ARDS, so I have added ARDS.

Trial Overview

Purpose

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

Primary Endpoints

Time to Clinical Improvement

description: Time to Clinical Improvement is defined as the time from randomization to either an increase of at least two points on a six category ordinal scale from the status at randomization or live discharge from the hospital.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
time_frame: at day 15

Other Endpoints

Time Untill Discharge

time_frame: during hospital admission (up to 28 days)

Time Until Independence From Supplemental Oxygen or Discharge

time_frame: during hospital admission (up to 28 days)

Time Until Independence From Invasive Ventilation

time_frame: during hospital admission (up to 54 days)

Number of Days in ICU

time_frame: during hospital admission (up to 28 days)

Number of Days in ICU in Patients Ventilated at Day of Randomization

time_frame: during hospital admission (up to 28 days)

Number of Days Without Supplemental Oxygen Use

time_frame: during hospital admission (up to 28 days)

Number of Invasive Ventilator Days

time_frame: during hospital admission (up to 28 days)

Number of Invasive Ventilator Days in Patients Ventilated at Day of Randomization

time_frame: during hospital admission (up to 28 days)

Number of Invasive Ventilator-free Days

time_frame: during hospital admission (up to 28 days)

Number of Invasive Ventilator-free Days in Patients Ventilated at Day of Randomization

time_frame: during hospital admission (up to 28 days)

Percentage of Days in ICU

description: Number of days the participants were ventilated, relative to the number of days participants were alive during the first 28 days after randomization. This was calculated as the number of days with need for invasive ventilation / number of days alive during first 28 days, multiplied by 100 (to obtain a percentage).
time_frame: first 28 days after randomization

Percentage of Invasive Ventilator Days

description: Number of days the participant spent in the ICU, relative to the number of days the patient was alive during the first 28 days after randomization. This was calculated as the number of days in ICU during first 28 days / number of days alive during first 28 days, multiplied by 100 (to obtain a percentage).
time_frame: the first 28 days after randomization

Time Until First Use of High-flow Oxygen Device, Ventilation, or Death

time_frame: during hospital admission (up to 28 days) [1]

Diseases Treated

Indication Qualifiers Patient Segments
Acute hypoxia treatment -
COVID 2019 infections treatment -
Cytokine release syndrome treatment -
Respiratory insufficiency treatment -
SARS-CoV-2 acute respiratory disease treatment -

Biomarker

NCT Number Biomarker Name Biomarker Function
NCT04330638 C-reactive protein (CRP) Eligibility Criteria, Outcome Measure
D-dimer Eligibility Criteria
Ferritin Eligibility Criteria, Outcome Measure
Interleukin 1 alpha (IL-1α) Outcome Measure
Interleukin 1 Beta (IL-1β) Outcome Measure
Interleukin-6 (IL-6) Official Title, Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Subjects

  • Subject Type patients
  • Number

    Planned: 342

    Actual: 342

  • Sex male & female
  • Age Group ≥ 18 years; adult

Patient 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

Patient 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.

Trial Details

Identifiers

Identifier Owner
NCT04330638 ClinicalTrials.gov: US National Institutes of Health
EudraCT2020-001500-41 European Clinical Trials Database
COV-AID -

Trial Dates

  • Initiation Dates

    Planned : 01 Apr 2020

    Actual : 03 Apr 2020

  • Primary Completion Dates

    Planned : 01 Jan 2021

    Actual : 20 Dec 2020

  • End Dates

    Planned : 12 Apr 2021

    Actual : 12 May 2021

Other Details

  • Design multicentre; open; parallel; prospective; randomised
  • Phase of Trial Phase III
  • Location Belgium
  • Focus Therapeutic Use

Interventions

Drugs Route Formulation
AnakinraPrimary Drug Subcutaneous Injection
SiltuximabPrimary Drug Intravenous Infusion, Injection
TocilizumabPrimary Drug Intravenous Infusion, Injection

Usual Care

Other: Usual Care (Usual Care)

Anakinra

Drug: Anakinra (Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first) Other Name: KINERET®

Anakinra + Siltuximab

Drug: Anakinra (Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first) Other Name: KINERET®
Drug: Siltuximab (Siltuximab will be given via single IV infusion at a dose of 11 mg/kg) Other Name: SYLVANT®

Anakinra + Tocilizumab

Drug: Anakinra (Anakinra will be given as a daily subcutaneous injection of 100 mg for 28 days or until hospital discharge, whichever is first) Other Name: KINERET®
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) Other Name: ROACTEMRA®

Siltuximab

Drug: Siltuximab (Siltuximab will be given via single IV infusion at a dose of 11 mg/kg) Other Name: SYLVANT®

Tocilizumab

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) Other Name: ROACTEMRA®

Trial Centres

Investigators

Investigator Centre Name Trial Centre Country
Anja Delporte
+32-9-3320228 anja.delporte@uzgent.be
show details
-
Bart Lambrecht, MD PhD
+32-9-3329110 bart.lambrecht@ugent.be
show details
University Hospital Ghent Belgium
Bart Lambrecht, MD, PhD
+32-9-3329110
bart.lambrecht@uzgent.be
show details
University Hospital, Ghent
-
CyrJean Yombi, MD PhD
jean.yombi@uclouvain.be
show details
University Hospital Saint-Luc Belgium
Elisabeth Dewaele
Elisabeth.dewaele@uzbrussel.be
show details
University Hospital Brussels Belgium
Elke Govaerts, MD
elke.govaerts@azstlucas.be
show details
AZ Sint-Lucas Belgium
Fabienne Liénart, MD
fabienne.lienart@chu-tivoli.be
show details
CHU Tivoli Belgium
Filip Moerman, MD
filip.moerman@chrcitadelle.be
show details
CHR de la Citadelle Belgium
HIRUZ CTU
C. Heymanslaan 10,
Ghent, 9000, Belgium
Tel:+3293320500
Fax:+3293320520
hiruz.ctu@uzgent.be
show details
University Hospital Ghent Belgium
Ingel Demedts, MD
ingel.demedts@azdelta.be
show details
AZ Delta Belgium
Jeroen Vanderhilst, MD
Jeroen.Vanderhilst@jessazh.be
show details
Jessa ZH Belgium
Maya Hites, MD PhD
maya.christina.hites@ulb.ac.be
show details
Erasmus University Hospital Belgium
Mesotten Dieter, MD
dieter.mesotten@zol.be
show details
Ziekenhuis Oost-Limurg Belgium
Necsoi Coca, MD
coca_necsoi@stpierre-bru.be
show details
University Hospital Saint-Pierre Belgium
Nicolas Deschryver, MD
nicolas.deschryver@cspo.be
show details
Cliniques Saint-Pierre Ottignies Belgium
Olivier Malaise, MD PhD
olivier.malaise@chuliege.be
show details
University Hospital Liège Belgium
Sebastien Anguille, MD
sebastien.anguille@uza.be
show details
University Hospital Antwerp Belgium
Stefaan Vandecasteele, MD
stefaan.vandecasteele@azsintjan.be
show details
AZ Sint-Jan Brugge Belgium

Centres

Centre Name Location Trial Centre Country
-
-
-
AZ Delta Roeselare Belgium
AZ Sint-Jan Brugge Brugge Belgium
AZ Sint-Lucas Gent Belgium
Belgium Health Care Knowledge Centre
-
-
CHR de la Citadelle Liège Belgium
CHU Tivoli La Louvière Belgium
Cliniques Saint-Pierre Ottignies Ottignies-Louvain-la-Neuve Belgium
Erasmus University Hospital Brussels Belgium
Jessa ZH Hasselt Belgium
University Hospital Antwerp Edegem Belgium
University Hospital Brussels Jette Belgium
University Hospital Ghent Ghent Belgium
University Hospital Ghent Gent Belgium
University Hospital Liège Liège Belgium
University Hospital Saint-Luc Brussels Belgium
University Hospital Saint-Pierre Brussels Belgium
University Hospital, Ghent
-
-
Ziekenhuis Oost-Limurg Genk Belgium

Trial History

Event Date Event Type Comment
16 Mar 2023 Other trial event Last checked against the ClinicalTrials.gov record. Updated 16 Mar 2023
15 Jul 2021 Status change - completed Status changed from active, no longer recruiting to completed. Updated 15 Jul 2021
15 Jul 2021 Other trial event Last checked against Eudra record. Updated 15 Jul 2021
02 Mar 2021 Biomarker Update Biomarkers information updated Updated 17 Sep 2021
01 Mar 2021 Completion date Planned End Date changed from 1 Mar 2021 to 12 Apr 2021. Updated 03 Mar 2021
14 Dec 2020 Other trial event For Hypoxic-respiratory-failure and respiratory-insufficiency narrower term is ARDS, so I have added ARDS. Updated 14 Dec 2020
08 Dec 2020 Other trial event Planned primary completion date changed from 1 Feb 2021 to 1 Jan 2021. Updated 14 Dec 2020
08 Dec 2020 Status change - active, no longer recruiting Status changed from recruiting to active, no longer recruiting. Updated 14 Dec 2020
03 Nov 2020 Completion date Planned End Date changed from 1 Dec 2020 to 1 Mar 2021. Updated 05 Nov 2020
03 Nov 2020 Other trial event Planned primary completion date changed from 1 Sep 2020 to 1 Feb 2021. Updated 05 Nov 2020
07 Apr 2020 Status change - recruiting Status changed from not yet recruiting to recruiting. Updated 09 Apr 2020
07 Apr 2020 Other trial event New source identified and integrated (European Clinical Trials Database;EudraCT2020-001500-41) Updated 07 Apr 2020
03 Apr 2020 New trial record New trial record Updated 03 Apr 2020

References

  1. ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2023;.

    Available from: URL: http://clinicaltrials.gov
  2. European Clinical Trials Database. Trial-Reg 2023;.

    Available from: URL: https://www.clinicaltrialsregister.eu
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