Clinical trial NCT04330638: Treatment of COVID-19 Patients With Anti-interleukin Drugs
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: Acute Lung Injury
Hypoxia
Acute Respiratory Distress Syndrome
Corona virus
COVID-19
SARS (Severe Acute Respiratory Syndrome)
Systemic Cytokine release Syndrome
Lead sponsor: University Hospital, Ghent
Sponsor class: OTHER
Collaborators: name: Belgium Health Care Knowledge Centre
First posted: 2020-04-01
Enrollment: 342
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Time to Clinical Improvement
timeFrame: at day 15
Secondary outcomes:
measure: Time Untill Discharge
timeFrame: during hospital admission (up to 28 days)
measure: Time Until Independence From Supplemental Oxygen or Discharge
timeFrame: during hospital admission (up to 28 days)
measure: Time Until Independence From Invasive Ventilation
timeFrame: during hospital admission (up to 54 days)
measure: Number of Days in ICU
timeFrame: during hospital admission (up to 28 days)
measure: Number of Days in ICU in Patients Ventilated at Day of Randomization
timeFrame: during hospital admission (up to 28 days)
measure: Number of Days Without Supplemental Oxygen Use
timeFrame: during hospital admission (up to 28 days)
measure: Number of Invasive Ventilator Days
timeFrame: during hospital admission (up to 28 days)
measure: Number of Invasive Ventilator Days in Patients Ventilated at Day of Randomization
timeFrame: during hospital admission (up to 28 days)
measure: Number of Invasive Ventilator-free Days
timeFrame: during hospital admission (up to 28 days)
measure: Number of Invasive Ventilator-free Days in Patients Ventilated at Day of Randomization
timeFrame: during hospital admission (up to 28 days)
measure: Percentage of Days in ICU
timeFrame: first 28 days after randomization
measure: Percentage of Invasive Ventilator Days
timeFrame: the first 28 days after randomization
measure: Time Until First Use of High-flow Oxygen Device, Ventilation, or Death
timeFrame: during hospital admission (up to 28 days)
Other outcomes:
Locations:
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge
city: Brussels
country: Belgium
facility: University Hospital Saint-Pierre
city: Brussels
country: Belgium
facility: Erasmus University Hospital
city: Brussels
country: Belgium
facility: University Hospital Saint-Luc
city: Edegem
country: Belgium
facility: University Hospital Antwerp
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limurg
city: Gent
country: Belgium
facility: AZ Sint-Lucas
city: Gent
country: Belgium
facility: University Hospital Ghent
city: Hasselt
country: Belgium
facility: Jessa ZH
city: Jette
country: Belgium
facility: University Hospital Brussels
city: La Louvière
country: Belgium
facility: CHU Tivoli
city: Liège
country: Belgium
facility: CHR de la Citadelle
city: Liège
country: Belgium
facility: University Hospital Liège
city: Ottignies-Louvain-la-Neuve
country: Belgium
facility: Cliniques Saint-Pierre Ottignies
city: Roeselare
country: Belgium
facility: AZ Delta
Study officials:
affiliation: University Hospital, Ghent
name: Bart Lambrecht, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Davidson M, Menon S, Chaimani A, Evrenoglou T, Ghosn L, Grana C, Henschke N, Cogo E, Villanueva G, Ferrand G, Riveros C, Bonnet H, Kapp P, Moran C, Devane D, Meerpohl JJ, Rada G, Hrobjartsson A, Grasselli G, Tovey D, Ravaud P, Boutron I. Interleukin-1 blocking agents for treating COVID-19. Cochrane Database Syst Rev. 2022 Jan 26;1(1):CD015308. doi: 10.1002/14651858.CD015308.
citation: Declercq J, Van Damme KFA, De Leeuw E, Maes B, Bosteels C, Tavernier SJ, De Buyser S, Colman R, Hites M, Verschelden G, Fivez T, Moerman F, Demedts IK, Dauby N, De Schryver N, Govaerts E, Vandecasteele SJ, Van Laethem J, Anguille S, van der Hilst J, Misset B, Slabbynck H, Wittebole X, Lienart F, Legrand C, Buyse M, Stevens D, Bauters F, Seys LJM, Aegerter H, Smole U, Bosteels V, Hoste L, Naesens L, Haerynck F, Vandekerckhove L, Depuydt P, van Braeckel E, Rottey S, Peene I, Van Der Straeten C, Hulstaert F, Lambrecht BN. Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial. Lancet Respir Med. 2021 Dec;9(12):1427-1438. doi: 10.1016/S2213-2600(21)00377-5. Epub 2021 Oct 29.
citation: Brands X, de Vries FMC, Uhel F, Haak BW, Peters-Sengers H, Schuurman AR, van Engelen TSR, Lutter R, Cremer OL, Bonten MJ, Schultz MJ, Scicluna BP, van der Poll T; MARS Consortium. Plasma Ferritin as Marker of Macrophage Activation-Like Syndrome in Critically Ill Patients With Community-Acquired Pneumonia. Crit Care Med. 2021 Nov 1;49(11):1901-1911. doi: 10.1097/CCM.0000000000005072.
citation: Maes B, Bosteels C, De Leeuw E, Declercq J, Van Damme K, Delporte A, Demeyere B, Vermeersch S, Vuylsteke M, Willaert J, Bolle 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.