Comparison of Tocilizumab Plus Dexamethasone vs. Dexamethasone for Patients With Covid-19

Study Overview
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Brief Summary
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The overall objective of the study is to determine the therapeutic effect and tolerance of Tocilizumab combined with Dexamethasone in patients with moderate, severe pneumonia or critical pneumonia associated with Coronavirus disease 2019 (COVID-19). Tocilizumab (TCZ) is an anti-human IL-6 receptor monoclonal antibody that inhibits signal transduction by binding sIL-6R and mIL-6R. The study has a cohort multiple Randomized Controlled Trials (cmRCT) design. Randomization will occur prior to offering Dexamethasone alone or Dexamethasone +Tocilizumab administration to patients enrolled in the CORIMUNO-19 cohort. Tocilizumab will be administered to consenting adult patients hospitalized with COVID-19 either diagnosed with moderate or severe pneumonia requiring no mechanical ventilation or critical pneumonia requiring mechanical ventilation. Patients who will chose not to receive Tocilizumab will receive standard of cares. Outcomes of Tocilizumab-treated patients will be compared with outcomes of standard of care (including Dexamethasone) treated patients

Official Title
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Comparison of Tocilizumab Plus Dexamethasone vs. Dexamethasone for Patients With Covid-19

Conditions
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Coronavirus Infection, SARS (Severe Acute Respiratory Syndrome), Virus Diseases, Coronaviridae Infections, Nidovirales Infections, RNA Virus Infections, Respiratory Tract Infections, Respiratory Tract Disease

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients included in the CORIMUNO-19 cohort Patients belonging to the following group: Requiring ≥ 3L/min of oxygen WHO progression scale = 5 No NIV or High flow Exclusion Criteria: Patients with exclusion criteria to the CORIMUNO-19 cohort. Known hypersensitivity to Tocilizumab or DXM or to any of their excipients. Pregnancy Current documented bacterial infection not controlled by antibiotics. certain evolving viral diseases (especially active herpes, chickenpox, shingles), psychotic states still not controlled by treatment, live vaccines in the previous 4 weeks, Active tuberculosis or disseminated strongyloidiasis Patient with any of following laboratory results out of the ranges detailed below at screening should be discussed depending of the medication: Absolute neutrophil count (ANC) ≤ 1.0 x 109/L Haemoglobin level: no limitation Platelets (PLT) < 50 G /L SGOT or SGPT > 5N

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dexamethasone<br>Dexamethasone : 10 mg once daily for the first five days (day 1 to day 5) then 5 mg per day for up to 5 days, 2.5mg per day for up to 4 days (or until oxygen supply independency if sooner) | Drug: Dexamethasone<br>* Dexamethasone : 10 mg once daily for the first five days (day 1 to day 5) then 5 mg per day for up to 5 days, 2.5mg per day for up to 4 days (or until oxygen supply independency if sooner)<br>|
| Experimental: Dexamethasone + Tocilizumab<br>Dexamethasone : 10 mg once daily for the first five days (day 1 to day 5) then 5 mg per day for up to 5 days, 2.5mg per day for up to 4 days (or until oxygen supply independency if sooner) +Tocilizumab 8mg/kg D1 and if no response (No decrease of oxygen requirement) a second fixed dose of 400mg wil be administered at D3 | Drug: Tocilizumab<br>* Tocilizumab 8mg/kg D1 and if no response (No decrease of oxygen requirement) a second fixed dose of 400mg wil be administered at D3<br>Drug: Dexamethasone<br>* Dexamethasone : 10 mg once daily for the first five days (day 1 to day 5) then 5 mg per day for up to 5 days, 2.5mg per day for up to 4 days (or until oxygen supply independency if sooner)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival without needs of invasive ventilation at day 14 | Survival without needs of invasive ventilation at day 14. Thus, events considered are mechanical (invasive) ventilation or death. A new DNR order will be considered as an event at the actual date of care limitation. | day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WHO progression scale at day 7 and 14 | WHO progression scale: Uninfected; non viral RNA detected: 0 Asymptomatic; viral RNA detected: 1 Symptomatic; Independent: 2 Symptomatic; Assistance needed: 3 Hospitalized; No oxygen therapy: 4 Hospitalized; oxygen by mask or nasal prongs: 5 Hospitalized; oxygen by NIV or High flow: 6 Intubation and Mechanical ventilation, pO2/FIO2>=150 OR SpO2/FIO2>=200: 7 Mechanical ventilation, (pO2/FIO2<150 OR SpO2/FIO2<200) OR vasopressors (norepinephrine >0.3 microg/kg/min): 8 Mechanical ventilation, pO2/FIO2<150 AND vasopressors (norepinephrine >0.3 microg/kg/min), OR Dialysis OR ECMO: 9 Dead: 10 | day 7 and day 14 | 
| Overall survival at 14, 28, 60 and 90 days | Overall survival | 14, 28, 60 and 90 days | 
| Cumulative incidence of discharge alive at 14 and 28 days | Cumulative incidence of discharge alive | 14 and 28 days | 
| Survival without needs of mechanical ventilation at day 1 | Survival without needs of mechanical ventilation at day 1. New DNR order (if given after the inclusion of the patient) will be considered as an event at the date of the DNR. | day 1 | 
| Cumulative incidence of oxygen supply independency at 14 and 28 days | Cumulative incidence of oxygen supply independency | 14 and 28 days | 
| Survival without needs of ventilator utilization at day 14 | Survival without needs of ventilator utilization (including non-invasive ventilation and Optiflow) at day 14 | 14 days |