COVID-19 patients with acute hypoxic respiratory failure and systemic cytokine release syndrome.
Conditions
Interventions
Trade Name: Kineret
Product Name: Kineret
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: ANAKINRA
CAS Number: 143090-92-0
Concentration unit: mg milligram(s)
Co
Sponsors
University Hospital Ghent
Eligibility
Sex/Gender
All
Inclusion 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 (1000 mcg/L and rising since last 24h -single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen device or mechanical ventilation -lymphopenia defined as 700 mcg/L and rising since last 24h -increased LDH (above 300 IU/L) and rising since last 24h -D-Dimers > 1000 ng/mL and rising since last 24h -CRP above 70 mg/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 and/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 = 18 years -Male or Female - Women of childbearing potential must have a negative serum pregnancy test pre-dose on day 1. Women 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. -Willing and able to provide informed consent or legal representative willing to provide informed consent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 171 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 171
Exclusion criteria
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 (> 8 mg methylprednisolone or equivalent for more than 1 month) 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, unless there are clear signs of cytokine release syndrome defined by LDH >300 IU/L and ferritin >700 ng/ml -history of (non-iatrogenic) 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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Study if blockade of IL-6 +/- IL-1 to block the cytokine storm and acute lung injury in comparison with usual care reduces time to clinical improvement as defined by an increase of more than 2 on the 6 point ordinal scale or discharge from the hospital;Secondary Objective: -to investigate whether treatment with either tocilizumab, siltuximab, anakinra or combinations thereof -improves oxygenation -causes defervescence, measured as time to first fever-free 48h period -improves features of secondary haemophagocytic lymphohistiocytosis -improves features of secondary haemophagocytic lymphohistiocytosis in relation to serum IL-6 and IL-1 -affects clinical outcome in relation to IL-6 and IL-1 levels -affects the rate of nosocomial infection -affects progression to mechanical ventilation, high oxygen delivery device, and/or ARDS in non-ventilated patients -affects length of dependency of ventilation in ventilated patients -affects all-cause mortality rate at 4 and 20 weeks post inclusion -affects long term 10-20 week follow up clinical status and lung function -is safe (number of AEs/SAEs) -When there is a significant association between IL-6 blockade and time to clinical improvement, tocilizumab and siltuximab will be compared versus usual care ;Primary end point(s): Time to clinical improvement (defined as the time from randomization to either an improvement of two points on a six-category ordinal scale measured daily till day 28 or discharge from the hospital or death) 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;Timepoint(s) of evaluation of this end point: 28 days | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 24h day 7 day 15 28 days after enrolment 12-20 weeks follow up 20 weeks post inclusion;Secondary end point(s): -Time since randomization until improvement in oxygenation, defined as independence from supplemental oxygen -Mean change in oxygenation defined by Pa02/FiO2 while breathing room air between day 1 and day 15 (or hospital discharge, whichever is first) -Number of days with hypoxia -Number of days of supplemental oxygen use -Time since randomization until absence of fever for more than 48h without antipyretics -Number of days with fever -Time since randomization until halving of CRP levels compared to peak value during trial -Time since randomization until halving of ferritin levels compared to peak value during trial -Incidence of AEs/SAEs during 28 days -Duration of hospital stay -Duration of hospital stay in survivors -Mean change in clinical sign score between day 1 and day 7 and between day 1 and day 15 (or on discharge, whichever is first) -Time since randomization until clinical sign score <6 maintained for 24h -Mean change of SOFA score between day 1 and day 7 or between day 1 and day 15 (or on discharge, whichever is first) -Mean change NEWS2 score between day 1 and day 7 or between day 1 and day 15 (or on discharge, whichever is first) -Time since randomization until NEWS2 score less than 2 for at least 24h - Percentage of patients reporting each severity rating on a 6-point ordinal scale 6-point Ordinal Scale at 15 days, in relation to serum IL-1 and IL-6 - Incidence of nosocomial bacterial or invasive fungal infection for 28 days after enrolment in trial - incidence of secondary haemophagocytic lymphohistiocytosis defined by Hs score Cardinal features of sHLH include unremitting fever, cytopenias, hyperferritinaemia, hypertriglyceridemia, pulmonary involvement can present as ARDS. Hs score calculation see http://saintantoine.aphp.fr/score/ -Incidence of secondary haemophagocyt | — |
Countries
Belgium
Contacts
Public ContactHIRUZ CTU
University Hospital Ghent
Outcome results
None listed