Tocilizumab for the Treatment of Cytokine Release Syndrome in Patients With COVID-19 (SARS-CoV-2 Infection)

Study Overview
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Brief Summary
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This phase III trial compares the effect of adding tocilizumab to standard of care versus standard of care alone in treating cytokine release syndrome (CRS) in patients with SARS-CoV-2 infection. CRS is a potentially serious disorder caused by the release of an excessive amount of substance that is made by cells of the immune system (cytokines) as a response to viral infection. Tocilizumab is used to decrease the body's immune response. Adding tocilizumab to standard of care may work better in treating CRS in patients with SARS-CoV-2 infection compared to standard of care alone.

Detailed Description
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PRIMARY OBJECTIVE: I. To decrease the length of invasive mechanical ventilation (MV) and rate of 30-day mortality from CRS due to SARS-CoV-2. SECONDARY OBJECTIVES: I. To decrease the rates of intensive care unit (ICU) transfer. II. To decrease the rate of invasive mechanical ventilation (MV). III. To decrease the length of ICU stay. IV. To decrease the rate of tracheostomy. V. Safety and efficacy of tociluzumab. VI. Biomarker assessment for response. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive tocilizumab intravenously (IV) every 12 hours for up to 3 doses in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care. ARM II: Patients receive standard of care.

Official Title
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Tociluzumab for Cytokine Release Syndrome With SARS-CoV-2: An Open-Labeled, Randomized Phase 3 Trial

Conditions
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Cerebrovascular Accident, Chronic Obstructive Pulmonary Disease, Chronic Renal Failure, Coronary Artery Disease, Diabetes Mellitus, Malignant Neoplasm, SARS Coronavirus 2 Infection

Intervention / Treatment
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* Other: Best Practice
* Biological: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis with SARS-CoV-2 by the currently available assays (Food and Drug Administration [FDA] approved) Should be hospitalized and exhibit at least one of the following predictors of mortality Age >= 65 years Current smoker (smoked >= 100 cigarettes in life and actively smoking) Chronic obstructive pulmonary disease (COPD) Diabetes Hypertension Coronary artery disease Cerebrovascular accident (CVA) Chronic renal disease (creatinine of >= 2 mg/dl) Cancer Patients that have C-reactive protein (CRP) >= 10 mg/L D-dimer >= 0.5 mg/L Procalcitonin >= 0.5 mg/L Lactate dehydrogenase (LDH) >= upper limit of normal (ULN) Patients or authorized family member willing to sign informed consent to participate in this study Exclusion Criteria: Pregnant or lactating women Hypersensitivity to tocilizumab Patients or authorized family member unwilling to sign informed consent to participate in this study Uncontrolled tuberculosis, or any uncontrolled fungal infection (eg: candidemia)

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 |
| --- | --- |
| Experimental: Arm I (tocilizumab, standard of care)<br>Patients receive tocilizumab IV every 12 hours for up to 3 doses in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care. | Other: Best Practice<br>* Receive standard of care<br>* Other names: standard therapy;Biological: Tocilizumab<br>* Given IV<br>* Other names: RoActemra;|
| Active Comparator: Arm II (standard of care)<br>Patients receive standard of care. | Other: Best Practice<br>* Receive standard of care<br>* Other names: standard therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 7-day length of invasive mechanical ventilation (MV) | The 7-day length of invasive MV for each arm will be estimated with 95% confidence intervals (CIs) using the exact binomial distribution. Their difference by the arms will be tested by Cochran-Mantel-Haenszel (CMH) test stratified by the age group and Sequential Organ Failure Assessment (SOFA) score at significance level of 0.05. | Up to 7 days | 
| 30-day mortality rate | Defined as death within 30-day after randomization. The 30-day mortality rate for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05. | Up to 30-day after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of intensive care (ICU) transfer | The rate of ICU transfer for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05. | Up to 2 years | 
| Rate of invasive mechanical ventilation | The rate of invasive mechanical ventilation for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05. | Up to 2 years | 
| Rate of tracheostomy | The rate of tracheostomy for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05. | Up to 2 years | 
| Length of ICU stay | Will first be described by median and inter-quartile, and then compared between two arms by Wilcoxon Sum-Rank test | Up to 2 years | 
| Length of hospital stay |  | Up 2 years |