Safety and Effectiveness Study of Tocilizumab in Patients With Severe COVID-19

Study Overview
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Brief Summary
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Retrospective observational cohort study to evaluate the safety and effectiveness of tocilizumab in the treatment of severe COVID-19 pneumonia

Detailed Description
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Since the appearence of the disease today known as COVID-19 there has been multiple interventions to try to gain knowledge on the subject and obtain a benefitial effect treating this condition. Tocilizumab, a monoclonal antibody targeting IL-6 receptor has arised as an alternative for the treament of COVID-19 pneumonia. It is a drug used for the treatment of rhemautoid arthritis and other autoimmune diseases as well as approved in recent years for the treatment of the cytokine release syndrome (CRS) in CAR-T therapy. It is based in this last premise that the benefitial effect on COVID-19 pneumonia has been sought of. According to investigation into the physiopathology of the virus, it is supposed to trigger the inflamattory cascade that generates damage to lungs and creates the most severe cases of the disease. These findings could imply that tocilizumab may serve to interrupt this cytokine storm and prevent the progression of the disease. The aim of the study is to evaluate the effectiveness and safety of tocilizumab in the treatment of severe cases of COVID-19. For that purpose, an observational retrospective cohort study has been designed comparing two populations that share the same indication for the treatment with tocilizumab. One having received the drug and the other in a close previous period of time that has not received it because of lack of availability or generalisation of its use. Mortality will be assesed as well as other variables such as need for mechanical ventilation and adverse effects of tocilizumab.

Official Title
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Safety and Effectiveness Observational Study of Anti IL-6 Tocilizumab in Hospital Admitted Patients With Severe COVID-19 Pneumonia.

Conditions
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Severe COVID 19 Pneumonia, Tocilizumab

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospital admitted patients with severe COVID-19 pneumonia (Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, respiratory frequency >30 breaths/min, or lung infiltrates >50%). Confirmed diagnosis of Covid-19 through qualitative polymerase-reverse transcriptase (qRT-PCR -GeneDX Co, Ltd o similar) or antigen rapid test. Patients who received tocilizumab or shared the same indication but did not received it (same period of time or previous close period) that: Progress in the requirement of supplemental oxygen (over 3L/m) and/or use of non-rebreathing mask with 8L/m or more to mantain a Sp02>= 94%. AND * Active inflammatory state defined as persistent fever > 38°C (defined as 2 or more measurements in a 24-hour period from hospital admission) despite the use of dexamethasone in the previous 48 hours OR C reactive Protein > 50 mg /dL OR D Dimer > 1000 ng/mL. Exclusion Criteria: Asymptomatic, mild or moderate COVID-19 disease. Patients with some type of immunosupression (HIV, use of immunomodulatory drugs, organ-trasplant receipt patients) Pregnant or breast-feeding Patients with augmented risk of bowel perforation (history of diverticulitis or bowel surgery in the three months prior to the study entrance date) Known severe allergic reactions to TCZ Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN) at screening Absolute neutrophil count (ANC) < 1000/mL at screening Platelet count < 50,000/mL at screening Positive Hepatitis B Surface (HbS) antigen Procalcitonine > 0,5 ng/mL Day of symptom onset before day 7 or after day 12 Patients with dementia Patients non eligible to progress to mechanical ventilation because of frailty/comorbidites according to medical decision.

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Tocilizumab<br>Group that received tocilizumab (8mg/kg, maximum dose 800 mg, only once) while being admitted with severe COVID-19 pneumonia. | Drug: Tocilizumab<br>* Tocilizumab received as a single intravenous infusion over the period of 60 minutes. Dose of 8 mg/kg, maximum dose of 800 mg.<br>|
| Non-tocilizumab<br>Group that did not receive tocilizumab but share the same indication according to the elegibility criteria for it as the tocilizumab group while admitted with severe COVID-19 pneumonia. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day mortality | 28-day mortality | 28 days from hospital admission | 
| Percentage of patients in invasive mechanical ventilation at day 28 | Percentage of patients that received invasive mechanical ventilation at day 28 following hospital admission. | 28 days from hospital admission | 
| Clinical status during follow-up at 28th day | Ordinal outcome with seven mutually exclusive categories to describe the patient's clinical status during follow-up. The six categories are: (1) Discharged or ready for discharge; (2) Admitted to non-ICU ward without oxygen; (3) admitted to non-ICU ward but requiring supplemental oxygen; (4) admitted to ICU or non ICU ward requiring high flow nasal canula or other non invasive mechanical ventilation; (5) admitted to ICU ward requiring invasive mechanical ventilation (6) admitted to ICU ward requiring extracorporeal membrane oxygenation or invasive mechanical ventilation plus other vital organ support; (7) death | 28th day from hospital admission | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate |  | Days 14 and 21 | 
| Percentage of patients in invasive mechanical ventilation at day 14 and 21 |  | Days 14 and 21 | 
| Percentage of patients with hospital discharge at day 7, 14, 21 and 28 |  | Days 7, 14, 21 and 28 | 
| Time to hospital discharge | Time from hospital admission to hospital discharge | Up to 60 days | 
| Percentage of patients admitted to ICU-ward at day 28 | Percentage of patients admitted to ICU-ward at day 28 from hospital admission | 28th day from hospital admission | 
| Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status |  | Up to 60 days | 
| Percentage of patients with need of tracheostomy at day 28 of hospital admission |  | 28th day from hospital admission | 
| Time to mechanical ventilation from hospital admission |  | Up to 28 days | 
| Days of ICU admission |  | Up to 60 days | 
| Time to ICU discharge from hospital admission | Time to ICU discharge from hospital admission in the patients subgroup that required ICU admission. | Up to 60 days | 
| Percentage of patients with adverse effects / serious adverse effects |  | Up to 28 days | 
| Percentage of superimposed infections |  | 28th day from hospital admission | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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covid 19, tocilizumab, severe pneumonia