Back to resultsSafety and Efficacy of Tocilizumab in Moderate to Severe COVID-19 With Inflammatory Markers (TOCIBRAS)
Primary Purpose
COVID, SARS Pneumonia, Cytokine Release Syndrome
Status
Terminated
Phase
Phase 3
Locations
Brazil
Study Type
Interventional
Intervention
Tocilizumab
Sponsored by
About this trial
This is an interventional treatment trial for COVID focused on measuring SARS-CoV 2, SARS Pneumonia, Tocilizumab, Cytokine release syndrom, Interleukin-6, Hyperinflammation
Eligibility Criteria
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
Sites / Locations
- UNIFESP
- HCOR -Hospital do Coracao
- HAOC - Hospital Alemao Oswaldo Cruz
- Beneficência Portuguesa de Sao Paulo
- HAOC - Hospital Alemao Oswaldo Cruz - unidade Vergueiro
- HIAE - Hospital Israelita Albert Einstein
- HSL - Hospital Sírio Libanês
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
Tocilizumab
Control arm
Arm Description
Single-dose tocilizumab of 8 mg/kg (maximum dose of 800mg). Best supportive care.
Best supportive care.
Outcomes
Primary Outcome Measures
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)
Secondary Outcome Measures
All-cause mortality
All-cause mortality from randomization to day 28
Hospital Mortality
Deaths that occur during hospital admission.
Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale
Improvement of SOFA scale of patients at day 8, 15 and 29 after randomization
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)
Ventilator free days
Days alive and free from mechanical ventilation since randomization
Time until oxygen support independence
Days from randomization to independence of oxygen support
Need of mechanical ventilation support
Number of patients that were not at mechanical ventilation at randomization and that required that support.
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.
Duration of hospitalization
Lenght of hospitalization stay in survivors (in days)
Other infections
Incidence of other infections (aside from SARS-CoV 2)
Incidence of thromboembolic events
Incidence of thromboembolic events in patients with COVID-19
Incidence of adverse events
Evaluation of adverse events, as well as serious and unexpected adverse events
Full Information
NCT ID
NCT04403685
First Posted
May 24, 2020
Last Updated
August 22, 2020
Sponsor
Beneficência Portuguesa de São Paulo
Collaborators
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
1. Study Identification
Unique Protocol Identification Number
NCT04403685
Brief Title
Safety and Efficacy of Tocilizumab in Moderate to Severe COVID-19 With Inflammatory Markers
Acronym
TOCIBRAS
Official Title
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)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2020
Overall Recruitment Status
Terminated
Why Stopped
Safety
Study Start Date
May 8, 2020 (Actual)
Primary Completion Date
July 8, 2020 (Actual)
Study Completion Date
July 21, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Beneficência Portuguesa de São Paulo
Collaborators
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
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID, SARS Pneumonia, Cytokine Release Syndrome
Keywords
SARS-CoV 2, SARS Pneumonia, Tocilizumab, Cytokine release syndrom, Interleukin-6, Hyperinflammation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Prospective, randomized, superiority, open-label, controlled trial. Randomization 1:1 to best supportive care (BSC) versus Tocilizumab + BSC
Masking
None (Open Label)
Allocation
Randomized
Enrollment
129 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tocilizumab
Arm Type
Experimental
Arm Description
Single-dose tocilizumab of 8 mg/kg (maximum dose of 800mg). Best supportive care.
Arm Title
Control arm
Arm Type
No Intervention
Arm Description
Best supportive care.
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
Actemra
Intervention Description
Single-dose infusion of 8 mg/kg. Maximum dose of 800 mg.
Primary Outcome Measure Information:
Title
Evaluation of clinical status
Description
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)
Time Frame
Day 15 of the trial
Secondary Outcome Measure Information:
Title
All-cause mortality
Description
All-cause mortality from randomization to day 28
Time Frame
29 days after the randomization
Title
Hospital Mortality
Description
Deaths that occur during hospital admission.
Time Frame
29 days after the randomization
Title
Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale
Description
Improvement of SOFA scale of patients at day 8, 15 and 29 after randomization
Time Frame
29 days after the randomization (evaluations at D8 and D15)
Title
Evaluation of clinical status
Description
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)
Time Frame
29 days after the randomization (evaluations at D8 and D29)
Title
Ventilator free days
Description
Days alive and free from mechanical ventilation since randomization
Time Frame
29 days after the randomization
Title
Time until oxygen support independence
Description
Days from randomization to independence of oxygen support
Time Frame
29 days after the randomization
Title
Need of mechanical ventilation support
Description
Number of patients that were not at mechanical ventilation at randomization and that required that support.
Time Frame
29 days after the randomization
Title
Days to mechanical ventilation support.
Description
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.
Time Frame
29 days after the randomization
Title
Duration of hospitalization
Description
Lenght of hospitalization stay in survivors (in days)
Time Frame
29 days after the randomization
Title
Other infections
Description
Incidence of other infections (aside from SARS-CoV 2)
Time Frame
29 days after the randomization
Title
Incidence of thromboembolic events
Description
Incidence of thromboembolic events in patients with COVID-19
Time Frame
29 days after the randomization
Title
Incidence of adverse events
Description
Evaluation of adverse events, as well as serious and unexpected adverse events
Time Frame
29 days after the randomization (specific evaluations at D8, D15 and D29)
Other Pre-specified Outcome Measures:
Title
Correlation of inflammatory tests and cytokines with clinical outcomes
Description
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
Time Frame
29 days after the randomization
Title
Exploratory evaluation of laboratory exams during hospitalization
Description
Evaluation the kinetics of hemostasia exams, inflammatory tests, cytokines, flow cytometry of blood cells, CBC, renal and liver exams
Time Frame
29 days after the randomization
Title
Evaluation of viral clearance of SARS-CoV2
Description
Evaluation of viral clearance of SARS-CoV2 using RT-PCR analysis of nasopharyngeal swab
Time Frame
Day 8 and 15 after randomization
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Viviane C Veiga, MD
Organizational Affiliation
Beneficência Portuguesa de Sao Paulo
Official's Role
Principal Investigator
Facility Information:
Facility Name
UNIFESP
City
São Paulo
State/Province
Sao Paulo
Country
Brazil
Facility Name
HCOR -Hospital do Coracao
City
Sao Paulo
State/Province
SP
ZIP/Postal Code
04004030
Country
Brazil
Facility Name
HAOC - Hospital Alemao Oswaldo Cruz
City
Sao Paulo
ZIP/Postal Code
01323001
Country
Brazil
Facility Name
Beneficência Portuguesa de Sao Paulo
City
Sao Paulo
ZIP/Postal Code
01323900
Country
Brazil
Facility Name
HAOC - Hospital Alemao Oswaldo Cruz - unidade Vergueiro
City
Sao Paulo
Country
Brazil
Facility Name
HIAE - Hospital Israelita Albert Einstein
City
Sao Paulo
Country
Brazil
Facility Name
HSL - Hospital Sírio Libanês
City
Sao Paulo
Country
Brazil
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33472855
Citation
Veiga VC, Prats JAGG, Farias DLC, Rosa RG, Dourado LK, Zampieri FG, Machado FR, Lopes RD, Berwanger O, Azevedo LCP, Avezum A, Lisboa TC, Rojas SSO, Coelho JC, Leite RT, Carvalho JC, Andrade LEC, Sandes AF, Pintao MCT, Castro CG Jr, Santos SV, de Almeida TML, Costa AN, Gebara OCE, de Freitas FGR, Pacheco ES, Machado DJB, Martin J, Conceicao FG, Siqueira SRR, Damiani LP, Ishihara LM, Schneider D, de Souza D, Cavalcanti AB, Scheinberg P; Coalition covid-19 Brazil VI Investigators. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021 Jan 20;372:n84. doi: 10.1136/bmj.n84.
Results Reference
derived
Learn more about this trial
Safety and Efficacy of Tocilizumab in Moderate to Severe COVID-19 With Inflammatory Markers
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