COVID, Cytokine Release Syndrome, SARS Pneumonia
Conditions
Keywords
SARS-CoV 2, SARS Pneumonia, Tocilizumab, Cytokine release syndrom, Interleukin-6, Hyperinflammation
Brief summary
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
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.
Interventions
DRUGTocilizumab
Single-dose infusion of 8 mg/kg. Maximum dose of 800 mg.
Sponsors
Hospital do Coracao
Hospital Israelita Albert Einstein
Hospital Sirio-Libanes
Hospital Alemão Oswaldo Cruz
Brazilian Research In Intensive Care Network
Hospital Moinhos de Vento
Brazilian Clinical Research Institute
Federal University of São Paulo
Beneficência Portuguesa de São Paulo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, randomized, superiority, open-label, controlled trial. Randomization 1:1 to best supportive care (BSC) versus Tocilizumab + BSC
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 1. Need for oxygen supplementation to keep SPO2 \> 93% OR need for mechanical ventilation for less than 24 hours before the randomization 2. At least two of the following inflammatory tests above the cutoff : 1. D-dimer \> 1,000 ng/mL 2. Reactive C protein \> 5 mg/dL 3. Ferritin \> 300 mg/dL 4. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of clinical status | Day 15 of the trial | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospital Mortality | 29 days after the randomization | Deaths that occur during hospital admission. |
| Time until oxygen support independence | 29 days after the randomization | Days from randomization to independence of oxygen support |
| Other infections | 29 days after the randomization | Incidence of other infections (aside from SARS-CoV 2) |
| Incidence of thromboembolic events | 29 days after the randomization | Incidence of thromboembolic events in patients with COVID-19 |
| Incidence of adverse events | 29 days after the randomization (specific evaluations at D8, D15 and D29) | Evaluation of adverse events, as well as serious and unexpected adverse events |
| Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale | 29 days after the randomization (evaluations at D8 and D15) | Improvement of SOFA scale of patients at day 8, 15 and 29 after randomization |
| Evaluation of clinical status | 29 days after the randomization (evaluations at D8 and D29) | 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) |
| Ventilator free days | 29 days after the randomization | Days alive and free from mechanical ventilation since randomization |
| All-cause mortality | 29 days after the randomization | All-cause mortality from randomization to day 28 |
| Need of mechanical ventilation support | 29 days after the randomization | Number of patients that were not at mechanical ventilation at randomization and that required that support. |
| Days to mechanical ventilation support. | 29 days after the randomization | 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. |
| Duration of hospitalization | 29 days after the randomization | Lenght of hospitalization stay in survivors (in days) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory evaluation of laboratory exams during hospitalization | 29 days after the randomization | Evaluation the kinetics of hemostasia exams, inflammatory tests, cytokines, flow cytometry of blood cells, CBC, renal and liver exams |
| Evaluation of viral clearance of SARS-CoV2 | Day 8 and 15 after randomization | Evaluation of viral clearance of SARS-CoV2 using RT-PCR analysis of nasopharyngeal swab |
| Correlation of inflammatory tests and cytokines with clinical outcomes | 29 days after the randomization | Correlation of inflammatory tests and cytokines with clinical outcomes: clinical status (ordinal scale), time to oxygen support independence, ventilator free days, need of mechanical ventilation and mortality |
Countries
Brazil
Outcome results
None listed