Clinical Trial of Sarilumab in Adults With COVID-19

Study Overview
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Brief Summary
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Early administration of sarilumab in hospitalized patients infected with COVID-19 who have pulmonary infiltrates and are at high risk of unfavorable evolution could decrease/prevent progression to acute respiratory distress syndrome (ARDS) requiring high flow nasal oxygenation (HFNO) or either invasive or non-invasive mechanical ventilation.

Official Title
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Clinical Trial of Sarilumab in Adults Hospitalized With COVID-19 Presenting Cytokine Release Syndrome

Conditions
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SARS, SARS-CoV 2

Intervention / Treatment
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* Drug: Sarilumab 200 MG/1.14 ML Subcutaneous Solution [KEVZARA]
* Drug: Sarilumab 400 MG/2.28 ML Subcutaneous Solution [KEVZARA]
* Drug: Best available treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years and <75 years Admission for confirmed respiratory symptoms to COVID-19 based on a positive PCR in a sample of the respiratory tract in the local laboratory in the absence of respiratory distress syndrome requiring ONAF or mechanical ventilation Interstitial pneumonia confirmed by chest radiography or CT IL-6 levels> 40 pg / ml. In its absence, D-Dimer (DD)> 1500 or> 1000 may be included if progressive increases are documented Negative pregnancy test in women of childbearing age Signature of informed consent Exclusion Criteria: SOFA score> 6 points Patient who, in the researcher's opinion, is not a subsidiary of invasive mechanical ventilation Neutrophil count <2 x 103 / μL Platelet count <100 x 103 / μL ALT or AST levels> 5 times the upper limit of normal Severe renal failure (CrCr <30 ml / min) Active bacterial infectious process Active tuberculosis, history of not completing treatment against tuberculosis, suspicion of extrapulmonary tuberculosis History of intestinal ulcer or diverticulitis History of hypersensitivity reactions to Sarilumab or its excipients Treatment with TNF antagonists Previous treatment with anti-IL6 in the previous 30 days Chronic prior treatment with corticosteroids at doses greater than 0.5 mg / kg / day of prednisone or equivalent. Yes, inhaled and topical corticosteroids are acceptable Concomitant treatment with immunomodulators, among which are Vitamin D or statins. Macrolides such as azithromycin are acceptable Patients on immunosuppressive treatment for any cause HIV-infected patients with CD4 <200 / mm3 Past or current history of autoimmune disease or systemic inflammatory disease Patients who have received or are planning therapy with immunomodulatory antibodies, including immunoglobulins Participation in any clinical trial that evaluated any investigational product in the last 3 months or less than 5 half-lives of the investigational product Pregnancy Any other condition that, in clinical judgment, prevents adherence to the patient's protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Experimental: Sarilumab 200 mg<br>Subjects treated with the best available treatment up to 14 days plus Sarilumab 200 mg single dose. | Drug: Sarilumab 200 MG/1.14 ML Subcutaneous Solution [KEVZARA]<br>* Best available treatment up to 14 days plus Sarilumab 200 mg<br>|
| Experimental: Sarilumab 400 mg<br>Subjects treated with the best available treatment up to 14 days plus Sarilumab 400 mg single dose. | Drug: Sarilumab 400 MG/2.28 ML Subcutaneous Solution [KEVZARA]<br>* Best available treatment up to 14 days plus Sarilumab 400 mg<br>|
| Active Comparator: Control<br>Subjects treated with the best available treatment up to 14 days. | Drug: Best available treatment<br>* Best available treatment up to 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilation requirements | Proportion of patients requiring or time (in days) until required: High flow nasal oxygenation (HFNO) Non-invasive mechanical ventilation type BiPAP Non-invasive mechanical ventilation type CPAP Invasive mechanical ventilation | At day 28 or when the subject is discharged (whichever occurs first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Crude mortality | Crude mortality at 28 days | At day 28 or when the subject is discharged (whichever occurs first) | 
| Time to clinical improvement | Time to clinical improvement: defined as the mean change or time in days from randomization to any of the following criteria: (i) improvement of two points on the ordinal scale of 7 points of severity or, (ii) hospital discharge with lifetime. The criteria reached before are used. The 7 point gravity scale includes the following categories: - Not hospitalized with normal activity - Not hospitalized but unable to have normal activity - Hospitalized, without requiring oxygen supplementation - Hospitalized, requiring oxygen supplementation - Hospitalized, requiring ONAF, non-invasive mechanical ventilation or both - Hospitalized requiring ECMO, invasive mechanical ventilation or both - Death | At day 28 or when the subject is discharged (whichever occurs first) | 
| Time until improvement in oxygenation | Time (in days) until improvement in oxygenation for at least 48 hours: Time to verify an increase in the SpO2 / FiO2 ratio with respect to the worst SpO2 / FiO2 prior to treatment with Sarilumab and stratified according to levels of IL-6 or DD Time to absence of oxygen requirement to maintain saturation in ambient air ≥ 93% Number of days in need of supplemental oxygen | At day 28 or when the subject is discharged (whichever occurs first) | 
| Proportion of patients requiring invasive mechanical ventilation | Proportion of patients requiring invasive mechanical ventilation in the trial | At day 28 or when the subject is discharged (whichever occurs first) | 
| Proportion of patients having negative COVID-19 CRP at each visit | Proportion of patients having negative COVID-19 CRP at each visit of the trial | At day 28 or when the subject is discharged (whichever occurs first) | 
| Mean of serum cytokine levels | Mean of serum cytokine levels: the panel of cytokines to quantify; IL1-��, IL1-β, IL6, IL8, IL10, IL12, IL18, IL38, INFɣ, TNF��, CCL2, CCL3, CCL4, MIF and PAI-1 | At day 28 or when the subject is discharged (whichever occurs first) | 
| Adverse events related to medication and its administration | Incidence of adverse events related to medication and its administration | At day 28 or when the subject is discharged (whichever occurs first) | 
| Incidence in the appearance of serious bacterial, fungal or opportunistic infections | Incidence in the appearance of serious bacterial, fungal or opportunistic infections in the subjects | At day 28 or when the subject is discharged (whichever occurs first) | 
| Incidence of perforation of the gastrointestinal tract | Incidence of perforation of the gastrointestinal tract in subjects | At day 28 or when the subject is discharged (whichever occurs first) | 
| Leukocyte and neutrophil count | Leukocyte and neutrophil count mean | At day 28 or when the subject is discharged (whichever occurs first) | 
| Hemoglobin levels | Mean hemoglobin levels | At day 28 or when the subject is discharged (whichever occurs first) | 
| Platelet count | Platelet count mean | At day 28 or when the subject is discharged (whichever occurs first) | 
| Levels of creatinemia | Average levels of creatinemia | At day 28 or when the subject is discharged (whichever occurs first) | 
| Bilirubin levels | Average bilirubin levels | At day 28 or when the subject is discharged (whichever occurs first) | 
| ALT and AST levels | ALT and AST average levels | At day 28 or when the subject is discharged (whichever occurs first) |