Safety and Efficacy of Tocilizumab in Moderate to Severe COVID-19 With Inflammatory Markers

Study Overview
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Brief Summary
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The trial evaluates the efficacy and safety of Tocilizumab, which rapidly reduces the inflammation process through inhibition of IL-6 in patients with moderate to severe COVID-19 with increased inflammatory markers. There will be two arms in the trial, one receiving the best supportive care, and the other receiving it plus tocilizumab. Patients will be followed until Day 29 after randomization.

Detailed Description
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Coalition VI (TOCIBRÁS) is a prospective phase III randomized controlled trial that evaluates the efficacy and safety of Tocilizumab, an antibody anti-IL-6 receptor in patients with moderate to severe COVID-19 with increased inflammatory markers. This is a superiority open-label study with two arms. The control arm receives the best supportive care, and the experimental receives it plus tocilizumab. Randomization is done centrally by REDCap 1:1. Patients will be followed until Day 29 after randomization.

Official Title
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Safety and Efficacy of Tocilizumab in Moderate to Severe COVID-19 and Increased Inflammatory Markers: a Phase III Randomized Clinical Trial (COVID-19 Coalition Brazil VI) (TOCIBRAS)

Conditions
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COVID, SARS Pneumonia, Cytokine Release Syndrome

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and females with 18 years and older Confirmed diagnosis of SARS-CoV 2 infection More than 3 days of symptoms related to COVID-19 Computed tomography (or Chest X-Ray) with COVID-19 alterations Both of the criteria Need for oxygen supplementation to keep SPO2 > 93% OR need for mechanical ventilation for less than 24 hours before the randomization At least two of the following inflammatory tests above the cutoff : D-dimer > 1,000 ng/mL Reactive C protein > 5 mg/dL Ferritin > 300 mg/dL Lactate dehydrogenase > upper level limit Exclusion Criteria: Need for mechanical ventilation for 24 hours or more before the randomization Hypersensitivity to tocilizumab Patients without therapeutic perspective or in palliative care Active non controlled infections Other clinical conditions that contraindicate tocilizumab, according to the assistant physician Low neutrophils count (< 0.5 x 109/L) Low platelets count (< 50 x 109/L) Liver disease, cirrhosis or elevated AST or ALT above 5 times the upper level limit Renal disease with estimate glomerular filtration below 30 mL/min/1.72 m2 (MDRD or CKD-EPI scores) Active diverticulitis Breastfeeding women Pregnancy

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
Interventional Model Description: Prospective, randomized, superiority, open-label, controlled trial. Randomization 1:1 to best supportive care (BSC) versus Tocilizumab + BSC
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab<br>Single-dose tocilizumab of 8 mg/kg (maximum dose of 800mg). Best supportive care. | Drug: Tocilizumab<br>* Single-dose infusion of 8 mg/kg. Maximum dose of 800 mg.<br>* Other names: Actemra;|
| No Intervention: Control arm<br>Best supportive care. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of clinical status | Evaluation of clinical status of patients on day 15 after randomization, defined by the Ordinal Scale of 7 points (score ranges from 1 to 7, with 7 being the worst score) | Day 15 of the trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | All-cause mortality from randomization to day 28 | 29 days after the randomization | 
| Hospital Mortality | Deaths that occur during hospital admission. | 29 days after the randomization | 
| Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale | Improvement of SOFA scale of patients at day 8, 15 and 29 after randomization | 29 days after the randomization (evaluations at D8 and D15) | 
| Evaluation of clinical status | Evaluation of clinical status of patients on the day 8, 22 and 29 after randomization, defined by the Ordinal Scale of 7 points (score ranges from 1 to 7, with 7 being the worst score) | 29 days after the randomization (evaluations at D8 and D29) | 
| Ventilator free days | Days alive and free from mechanical ventilation since randomization | 29 days after the randomization | 
| Time until oxygen support independence | Days from randomization to independence of oxygen support | 29 days after the randomization | 
| Need of mechanical ventilation support | Number of patients that were not at mechanical ventilation at randomization and that required that support. | 29 days after the randomization | 
| Days to mechanical ventilation support. | Number of days to mechanical ventilation for patients that were not receiving it at randomization. For patients that were not in mechanical ventilation at randomization: number of days until that support was required. | 29 days after the randomization | 
| Duration of hospitalization | Lenght of hospitalization stay in survivors (in days) | 29 days after the randomization | 
| Other infections | Incidence of other infections (aside from SARS-CoV 2) | 29 days after the randomization | 
| Incidence of thromboembolic events | Incidence of thromboembolic events in patients with COVID-19 | 29 days after the randomization | 
| Incidence of adverse events | Evaluation of adverse events, as well as serious and unexpected adverse events | 29 days after the randomization (specific evaluations at D8, D15 and D29) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV 2, SARS Pneumonia, Tocilizumab, Cytokine release syndrom, Interleukin-6, Hyperinflammation