| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| COVID-19 patients with acute hypoxic respiratory failure and systemic cytokine release syndrome. |
|
| E.1.1.1 | Medical condition in easily understood language |
| COVID-19 patients with acute hypoxic respiratory failure and systemic cytokine release syndrome. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
-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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
-serum ferritin concentration >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 <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 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 |
|
| E.4 | Principal 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) |
|
| E.5 End points |
| E.5.1 | 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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 haemophagocytic lymphohistiocytosis defined by Hs score (Hs score calculation see http://saintantoine.aphp.fr/score/) in relation to serum IL-1 and IL-6
-Time since randomization until first use of high-flow oxygen devices, non-invasive or invasive mechanical ventilation in non-ventilated patients
-Time since randomization until first use of salvage systemic steroids in ventilated patients
-Ventilator-free days over 28 days from inclusion date
-Duration of mechanical ventilation in ventilated patients
-Duration of ICU stay in patients that enrolled in trial while already on invasive or non-invasive mechanical ventilation
-Time to progression to ARDS in ventilated patients
criteria-defined ARDS (according to the American-European Consensus Conference (AECC) diagnostic criteria for ARDS: acute onset; ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) of 200mmHg or less, regardless of positive end-expiratory pressure; bilateral infiltrates seen on frontal chest radiograph; and pulmonary artery wedge pressure of 18 mm Hg or less when measured, or no clinical evidence of left atrial hypertension)
-Time to progression to ARDS in ventilated patients according to IL-1 and IL-6
-All-cause mortality rate at 28 days post inclusion (excluding group that entered during ventilation)
-Percentage of patients in clinical status on 6-point Ordinal Scale at 10-20 weeks follow up
-Incidence of lung function abnormalities at 10-20 weeks follow up
-Incidence of lung fibrosis on chest CT scan at 10-20 weeks follow up
-All cause mortality at 20 weeks post inclusion for the entire study population |
|
| E.5.2.1 | 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 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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