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

• ClinicalTrials.gov Identifier: NCT04330638
• Recruitment Status: Active, not recruiting
• First Posted: April 1, 2020
• Last Update Posted: March 2, 2021
• Sponsor: University Hospital, Ghent
• Collaborator: Belgium Health Care Knowledge Centre
• Information provided by (Responsible Party): Bart N. Lambrecht, University Hospital, Ghent

Study Description

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

Condition or disease	Intervention/treatment	Phase
COVID-19	Other: Usual Care; Drug: Anakinra; Drug: Siltuximab; Drug: Tocilizumab	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 342 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: April 3, 2020
• Actual Primary Completion Date: December 18, 2020
• Estimated Study Completion Date: April 12, 2021

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Usual Care	Other: Usual Care; Usual Care
Active Comparator: 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®
Active Comparator: Siltuximab	Drug: Siltuximab; Siltuximab will be given via single IV infusion at a dose of 11 mg/kg; Other Name: SYLVANT®
Active Comparator: 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®
Active Comparator: 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®
Active Comparator: 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®

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. Time to improvement in oxygenation [ Time Frame: during hospital admission (up to 28 days) ]
   defined as independece from supplemental oxygen
2. 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
3. Number of days with hypoxia [ Time Frame: during hospital admission (up to 28 days) ]
4. Number of days of supplemental oxygen use [ Time Frame: during hospital admission (up to 28 days) ]
5. Time to absence fever for more than 48h without antipyretics [ Time Frame: during hospital admission (up to 28 days) ]
6. Number of days with fever [ Time Frame: during hospital admission (up to 28 days) ]
7. Time to halving of CRP levels compared to peak value during trial [ Time Frame: during hospital admission (up to 28 days) ]
8. Time to halving of ferritin levels compared to peak value during trial [ Time Frame: during hospital admission (up to 28 days) ]
9. Incidence of AEs (Adverse Events) [ Time Frame: during hospital admission (up to 28 days) ]
10. Incidence of SAEs (Serious Adverse Events) [ Time Frame: during hospital admission (up to 28 days) ]
11. Duration of hospital stay [ Time Frame: during hospital admission (up to 28 days) ]
12. Duration of hospital stay in survivors [ Time Frame: during hospital admission (up to 28 days) ]
13. 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)
14. 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)
15. 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
16. 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
17. Incidence of nosocomial bacterial or invasive fungal infection [ Time Frame: during hospital admission (up to 28 days) ]
18. incidence of secondary haemophagocytic lymphohistiocytosis [ Time Frame: during hospital admission (up to 28 days) ]
    defined by Hs (Hemophagocytic Syndrome) score
19. Incidence of secondary haemophagocytic lymphohistiocytosisscore in relation to serum IL-1 [ Time Frame: during hospital admission (up to 28 days) ]
    defined by Hs score
20. Incidence of secondary haemophagocytic lymphohistiocytosis in relation to serum IL-6 [ Time Frame: during hospital admission (up to 28 days) ]
    defined by Hs score
21. 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) ]
22. Time to first use of salvage systemic steroids in ventilated patients [ Time Frame: during hospital admission (up to 28 days) ]
23. Number of ventilator free days [ Time Frame: during hospital admission (up to 28 days) ]
24. Duration of mechanical ventilation in ventilated patients [ Time Frame: during hospital admission (up to 28 days) ]
25. 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) ]
26. Time to progression to ARDS in ventilated patients, according to the adapted Berlin criteria [ Time Frame: during hospital admission (up to 28 days) ]
27. Time to progression to ARDS in ventilated patients according to IL-1 [ Time Frame: during hospital admission (up to 28 days) ]
28. Time to progression to ARDS in ventilated patients according to IL-6 [ Time Frame: during hospital admission (up to 28 days) ]
29. All-cause mortality rate (excluding group that entered during ventilation) [ Time Frame: during hospital admission (up to 28 days) ]
30. Percentage of patients in clinical status on 6-point Ordinal Scale [ Time Frame: at 10-20 weeks follow-up ]
31. Incidence of lung function abnormalities [ Time Frame: at 10-20 weeks follow-up ]
32. Incidence of lung fibrosis on chest CT scan [ Time Frame: at 10-20 weeks follow-up ]
33. All-cause mortality rate [ Time Frame: at 10-20 weeks follow-up ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Belgium

AZ Sint-Jan Brugge

Brugge, Belgium, 8000

University Hospital Saint-Pierre

Brussels, Belgium, 1000

Erasmus University Hospital

Brussels, Belgium, 1070

University Hospital Saint-Luc

Brussels, Belgium, 1200

University Hospital Antwerp

Edegem, Belgium, 2650

Ziekenhuis Oost-Limurg

Genk, Belgium, 3600

AZ Sint-Lucas

Gent, Belgium, 9000

University Hospital Ghent

Gent, Belgium, 9000

Jessa ZH

Hasselt, Belgium, 3500

University Hospital Brussels

Jette, Belgium, 1090

CHU Tivoli

La Louvière, Belgium, 7100

CHR de la Citadelle

Liège, Belgium, 4000

University Hospital Liège

Liège, Belgium, 4000

Cliniques Saint-Pierre Ottignies

Ottignies-Louvain-la-Neuve, Belgium, 1340

AZ Delta

Roeselare, Belgium, 8800

Sponsors and Collaborators

University Hospital, Ghent

Belgium Health Care Knowledge Centre

Investigators

• Principal Investigator: Bart Lambrecht, MD, PhD; University Hospital, Ghent

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Bart N. Lambrecht, Professor in Pulmonology, Director VIB-Inflammational Research Center, University Hospital, Ghent
• ClinicalTrials.gov Identifier: NCT04330638
• Other Study ID Numbers: COV-AID
• First Posted: April 1, 2020
• Last Update Posted: March 2, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Bart N. Lambrecht, University Hospital, Ghent:

Acute Lung Injury; Hypoxia; Acute Respiratory Distress Syndrome; Corona virus; COVID-19; SARS (Severe Acute Respiratory Syndrome); Systemic Cytokine release Syndrome

Additional relevant MeSH terms:

Siltuximab; Interleukin 1 Receptor Antagonist Protein; Antirheumatic Agents; Antineoplastic Agents