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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: Recruiting
Phase of Trial: Phase III

Latest Information Update: 28 Apr 2020

At a glance

  • Drugs Anakinra (Primary) ; Siltuximab (Primary) ; Tocilizumab (Primary)
  • Indications COVID 2019 infections
  • Focus Therapeutic Use
  • Acronyms COV-AID
  • Most Recent Events

    • 07 Apr 2020 Status changed from not yet recruiting to recruiting.
    • 03 Apr 2020 New trial record

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: defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the hospital:
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
time_frame: at day 15

Other Endpoints

Time to improvement in oxygenation

description: defined as independece from supplemental oxygen
time_frame: during hospital admission (up to 28 days)

Mean change in oxygenation

description: defined by Pa02/FiO2 ratio while breading room air
time_frame: day 1, day 15 or hospital discharge, whichever is first

Number of days with hypoxia

time_frame: during hospital admission (up to 28 days)

Number of days of supplemental oxygen use

time_frame: during hospital admission (up to 28 days)

Time to absence fever for more than 48h without antipyretics

time_frame: during hospital admission (up to 28 days)

Number of days with fever

time_frame: during hospital admission (up to 28 days)

Time to halving of CRP levels compared to peak value during trial

time_frame: during hospital admission (up to 28 days)

Time to halving of ferritin levels compared to peak value during trial

time_frame: during hospital admission (up to 28 days)

Incidence of AEs (Adverse Events)

time_frame: during hospital admission (up to 28 days)

Incidence of SAEs (Serious Adverse Events)

time_frame: during hospital admission (up to 28 days)

Duration of hospital stay

time_frame: during hospital admission (up to 28 days)

Duration of hospital stay in survivors

time_frame: during hospital admission (up to 28 days)

Mean change in clinical sign score between day 1 and day 7

description: Clinical sign score: 0( best) - 18 (worse)
time_frame: day 1, day 7 or hospital discharge, whichever is first

Mean change in clinical sign score between day 1 and day 15

description: Clinical sign score: 0( best) - 18 (worse)
time_frame: day 1, day 15 or hospital discharge, whichever is first

Time to clinical sign score <6 maintained for 24h

description: Clinical sign score: 0( best) - 18 (worse)
time_frame: during hospital admission (up to 28 days)

Mean change of SOFA score (Sequential Organ Failure Assessment) between day 1 and day 7

description: SOFA score: 0 (best) - 24 (worse)
time_frame: Day 1, day 7or hospital discharge, whichever is first

Mean change of SOFA score between day 1 and day 15

description: SOFA score: 0 (best) - 24 (worse)
time_frame: day 1, day 15 or hospital discharge, whichever is first

Mean change NEWS2 (National Early Warning) score between day 1 and day 7

description: NEWS2 score: 0 (best) - 24 (worse)
time_frame: day 1, day 7 or hospital discharge, whichever is first

Mean change NEWS2 score between day 1 and day 15

description: NEWS2 score: 0 (best) - 24 (worse)
time_frame: day 1, day 15 or hospital discharge, whichever is first

Percentage of patients reporting each severity rating on a 6-point ordinal scale in relation to serum IL-1

description: 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
time_frame: at day 15 or hospital discharge, whichever is first

Percentage of patients reporting each severity rating on a 6-point ordinal scale in relation to serum IL-6

description: 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
time_frame: at day 15 or hospital discharge, whichever is first

Incidence of nosocomial bacterial or invasive fungal infection

time_frame: during hospital admission (up to 28 days)

incidence of secondary haemophagocytic lymphohistiocytosis

description: defined by Hs (Hemophagocytic Syndrome) score
time_frame: during hospital admission (up to 28 days)

Incidence of secondary haemophagocytic lymphohistiocytosisscore in relation to serum IL-1

description: defined by Hs score
time_frame: during hospital admission (up to 28 days)

Incidence of secondary haemophagocytic lymphohistiocytosis in relation to serum IL-6

description: defined by Hs score
time_frame: during hospital admission (up to 28 days)

Time to first use of high-flow oxygen devices, non-invasive or invasive mechanical ventilation in non-ventilated patients

time_frame: during hospital admission (up to 28 days)

Time to first use of salvage systemic steroids in ventilated patients

time_frame: during hospital admission (up to 28 days)

Number of ventilator free days

time_frame: during hospital admission (up to 28 days)

Duration of mechanical ventilation in ventilated patients

time_frame: during hospital admission (up to 28 days)

Duration of ICU stay in patients that enrolled in trial while already on invasive or non-invasive mechanical ventilation

time_frame: during hospital admission (up to 28 days)

Time to progression to ARDS in ventilated patients

time_frame: during hospital admission (up to 28 days)

Time to progression to ARDS in ventilated patients according to IL-1

time_frame: during hospital admission (up to 28 days)

Time to progression to ARDS in ventilated patients according to IL-6

time_frame: during hospital admission (up to 28 days)

All-cause mortality rate (excluding group that entered during ventilation)

time_frame: during hospital admission (up to 28 days)

Percentage of patients in clinical status on 6-point Ordinal Scale

time_frame: at 10-20 weeks follow-up

Incidence of lung function abnormalities

time_frame: at 10-20 weeks follow-up

Incidence of lung fibrosis on chest CT scan

time_frame: at 10-20 weeks follow-up

All-cause mortality rate

time_frame: at 10-20 weeks follow-up [1]

Diseases Treated

Indication Qualifiers Patient Segments
COVID 2019 infections treatment -

Subjects

  • Subject Type patients
  • Number

    Planned: 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 - clinical frailty scale above 3 - 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 : 01 Apr 2020

  • Primary Completion Dates

    Planned : 01 Sep 2020

  • End Dates

    Planned : 01 Dec 2020

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
28 Apr 2020 Other trial event Last checked against Eudra record. Updated 28 Apr 2020
27 Apr 2020 Other trial event Last checked against the ClinicalTrials.gov record. Updated 27 Apr 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 2016;.

    Available from: URL: http://clinicaltrials.gov
  2. European Clinical Trials Database. Trial-Reg 2016;.

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