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Treatment of COVID-19 Patients With Anti-interleukin Drugs (COV-AID)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04330638
Recruitment Status : Active, not recruiting
First Posted : April 1, 2020
Last Update Posted : March 2, 2021
Sponsor:
Collaborator:
Belgium Health Care Knowledge Centre
Information provided by (Responsible Party):
Bart N. Lambrecht, University Hospital, Ghent

Tracking Information
First Submitted Date  ICMJE March 31, 2020
First Posted Date  ICMJE April 1, 2020
Last Update Posted Date March 2, 2021
Actual Study Start Date  ICMJE April 3, 2020
Actual Primary Completion Date December 18, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 3, 2020)
Time to Clinical Improvement [ Time Frame: at day 15 ]
defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the hospital:
  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
Original Primary Outcome Measures  ICMJE
 (submitted: March 31, 2020)
Time to Clinical Improvement [ Time Frame: at day 15 ]
defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the hospital
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2020)
  • Time to improvement in oxygenation [ Time Frame: during hospital admission (up to 28 days) ]
    defined as independece from supplemental oxygen
  • Mean change in oxygenation [ Time Frame: day 1, day 15 or hospital discharge, whichever is first ]
    defined by Pa02/FiO2 ratio while breading room air
  • 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 of SOFA score (Sequential Organ Failure Assessment) between day 1 and day 7 [ Time Frame: Day 1, day 7or hospital discharge, whichever is first ]
    SOFA score: 0 (best) - 24 (worse)
  • Mean change of SOFA score between day 1 and day 15 [ Time Frame: day 1, day 15 or hospital discharge, whichever is first ]
    SOFA score: 0 (best) - 24 (worse)
  • Percentage of patients reporting each severity rating on a 6-point ordinal scale in relation to serum IL-1 [ Time Frame: at day 15 or hospital discharge, whichever is first ]
    6-point ordinal scale:
    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
  • Percentage of patients reporting each severity rating on a 6-point ordinal scale in relation to serum IL-6 [ Time Frame: at day 15 or hospital discharge, whichever is first ]
    6-point ordinal scale:
    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
  • Incidence of nosocomial bacterial or invasive fungal infection [ Time Frame: during hospital admission (up to 28 days) ]
  • incidence of secondary haemophagocytic lymphohistiocytosis [ Time Frame: during hospital admission (up to 28 days) ]
    defined by Hs (Hemophagocytic Syndrome) score
  • Incidence of secondary haemophagocytic lymphohistiocytosisscore in relation to serum IL-1 [ Time Frame: during hospital admission (up to 28 days) ]
    defined by Hs score
  • Incidence of secondary haemophagocytic lymphohistiocytosis in relation to serum IL-6 [ Time Frame: during hospital admission (up to 28 days) ]
    defined by Hs score
  • 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, according to the adapted Berlin criteria [ 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 31, 2020)
  • Time to improvement in oxygenation [ Time Frame: during hospital admission (up to 28 days) ]
    defined as independece from supplemental oxygen
  • Mean change in oxygenation [ Time Frame: day 1, day 15 or hospital discharge, whichever is first ]
    defined by Pa02/FiO2 ratio while breading room air
  • 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 [ Time Frame: day 1, day 7 or hospital discharge, whichever is first ]
  • Mean change in clinical sign score between day 1 and day 15 [ Time Frame: day 1, day 15 or hospital discharge, whichever is first ]
  • Time to clinical sign score <6 maintained for 24h [ Time Frame: during hospital admission (up to 28 days) ]
  • Mean change of SOFA score (Sequential Organ Failure Assessment) between day 1 and day 7 [ Time Frame: Day 1, day 7or hospital discharge, whichever is first ]
  • Mean change of SOFA score between day 1 and day 15 [ 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 [ Time Frame: day 1, day 7 or hospital discharge, whichever is first ]
  • Mean change NEWS2 score between day 1 and day 15 [ 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 [ 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 [ 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 [ Time Frame: during hospital admission (up to 28 days) ]
    defined by Hs (Hemophagocytic Syndrome) score
  • Incidence of secondary haemophagocytic lymphohistiocytosisscore in relation to serum IL-1 [ Time Frame: during hospital admission (up to 28 days) ]
    defined by Hs score
  • Incidence of secondary haemophagocytic lymphohistiocytosis in relation to serum IL-6 [ Time Frame: during hospital admission (up to 28 days) ]
    defined by Hs score
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of COVID-19 Patients With Anti-interleukin Drugs
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Other: Usual Care
    Usual Care
  • 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®
  • 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®
Study Arms  ICMJE
  • Placebo Comparator: Usual Care
    Intervention: Other: Usual Care
  • Active Comparator: Anakinra
    Intervention: Drug: Anakinra
  • Active Comparator: Siltuximab
    Intervention: Drug: Siltuximab
  • Active Comparator: Anakinra + Siltuximab
    Interventions:
    • Drug: Anakinra
    • Drug: Siltuximab
  • Active Comparator: Tocilizumab
    Intervention: Drug: Tocilizumab
  • Active Comparator: Anakinra + Tocilizumab
    Interventions:
    • Drug: Anakinra
    • Drug: Tocilizumab
Publications * Maes B, Bosteels C, De Leeuw E, Declercq J, Van Damme K, Delporte A, Demeyere B, Vermeersch S, Vuylsteke M, Willaert J, Bollé 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. Erratum in: Trials. 2020 Jun 22;21(1):556.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 31, 2020)
342
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 12, 2021
Actual Primary Completion Date December 18, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04330638
Other Study ID Numbers  ICMJE COV-AID
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Bart N. Lambrecht, University Hospital, Ghent
Study Sponsor  ICMJE University Hospital, Ghent
Collaborators  ICMJE Belgium Health Care Knowledge Centre
Investigators  ICMJE
Principal Investigator: Bart Lambrecht, MD, PhD University Hospital, Ghent
PRS Account University Hospital, Ghent
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP