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
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
- 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.
Most Recent Events
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 |
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
|
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|
|
Bart Lambrecht, MD PhD
+32-9-3329110 bart.lambrecht@ugent.be
show details
|
University Hospital Ghent | Belgium |
Bart Lambrecht, MD, PhD
+32-9-3329110
show details
bart.lambrecht@uzgent.be |
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,
show details
Ghent, 9000, Belgium Tel:+3293320500 Fax:+3293320520 hiruz.ctu@uzgent.be |
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
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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
-
ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2023;.
Available from: URL: http://clinicaltrials.gov -
European Clinical Trials Database. Trial-Reg 2023;.
Available from: URL: https://www.clinicaltrialsregister.eu
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