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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04403685
Recruitment Status : Terminated (Safety)
First Posted : May 27, 2020
Last Update Posted : August 26, 2020
Sponsor:
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
Information provided by (Responsible Party):
Dr Rozana Mesquita Ciconelli, Beneficência Portuguesa de São Paulo

Study Description
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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.

Condition or disease Intervention/treatment Phase
COVID SARS Pneumonia Cytokine Release Syndrome Drug: Tocilizumab Phase 3

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 129 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, randomized, superiority, open-label, controlled trial. Randomization 1:1 to best supportive care (BSC) versus Tocilizumab + BSC
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : May 8, 2020
Actual Primary Completion Date : July 8, 2020
Actual Study Completion Date : July 21, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Tocilizumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Tocilizumab
Single-dose tocilizumab of 8 mg/kg (maximum dose of 800mg). Best supportive care.
 Drug: Tocilizumab
Single-dose infusion of 8 mg/kg. Maximum dose of 800 mg.
Other Name: Actemra
No Intervention: Control arm
Best supportive care.


Outcome Measures
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Primary Outcome Measures :
  1. Evaluation of clinical status [ Time Frame: 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 Outcome Measures :
  1. All-cause mortality [ Time Frame: 29 days after the randomization ]
    All-cause mortality from randomization to day 28

  2. Hospital Mortality [ Time Frame: 29 days after the randomization ]
    Deaths that occur during hospital admission.

  3. Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale [ Time Frame: 29 days after the randomization (evaluations at D8 and D15) ]
    Improvement of SOFA scale of patients at day 8, 15 and 29 after randomization

  4. Evaluation of clinical status [ Time Frame: 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)

  5. Ventilator free days [ Time Frame: 29 days after the randomization ]
    Days alive and free from mechanical ventilation since randomization

  6. Time until oxygen support independence [ Time Frame: 29 days after the randomization ]
    Days from randomization to independence of oxygen support

  7. Need of mechanical ventilation support [ Time Frame: 29 days after the randomization ]
    Number of patients that were not at mechanical ventilation at randomization and that required that support.

  8. Days to mechanical ventilation support. [ Time Frame: 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.


  9. Duration of hospitalization [ Time Frame: 29 days after the randomization ]
    Lenght of hospitalization stay in survivors (in days)

  10. Other infections [ Time Frame: 29 days after the randomization ]
    Incidence of other infections (aside from SARS-CoV 2)

  11. Incidence of thromboembolic events [ Time Frame: 29 days after the randomization ]
    Incidence of thromboembolic events in patients with COVID-19

  12. Incidence of adverse events [ Time Frame: 29 days after the randomization (specific evaluations at D8, D15 and D29) ]
    Evaluation of adverse events, as well as serious and unexpected adverse events


Other Outcome Measures:
  1. Correlation of inflammatory tests and cytokines with clinical outcomes [ Time Frame: 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

  2. Exploratory evaluation of laboratory exams during hospitalization [ Time Frame: 29 days after the randomization ]
    Evaluation the kinetics of hemostasia exams, inflammatory tests, cytokines, flow cytometry of blood cells, CBC, renal and liver exams

  3. Evaluation of viral clearance of SARS-CoV2 [ Time Frame: Day 8 and 15 after randomization ]
    Evaluation of viral clearance of SARS-CoV2 using RT-PCR analysis of nasopharyngeal swab


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

    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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04403685


Locations
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Brazil
UNIFESP
São Paulo, Sao Paulo, Brazil
HCOR -Hospital do Coracao
Sao Paulo, SP, Brazil, 04004030
HAOC - Hospital Alemao Oswaldo Cruz
Sao Paulo, Brazil, 01323001
Beneficência Portuguesa de Sao Paulo
Sao Paulo, Brazil, 01323900
HAOC - Hospital Alemao Oswaldo Cruz - unidade Vergueiro
Sao Paulo, Brazil
HIAE - Hospital Israelita Albert Einstein
Sao Paulo, Brazil
HSL - Hospital Sírio Libanês
Sao Paulo, Brazil
Sponsors and Collaborators
Beneficência Portuguesa de São Paulo
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
Investigators
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Principal Investigator: Viviane C Veiga, MD Beneficência Portuguesa de Sao Paulo
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Dr Rozana Mesquita Ciconelli, Head of research team, Beneficência Portuguesa de São Paulo
ClinicalTrials.gov Identifier: NCT04403685    
Other Study ID Numbers: TOCIBRAS
First Posted: May 27, 2020    Key Record Dates
Last Update Posted: August 26, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Dr Rozana Mesquita Ciconelli, Beneficência Portuguesa de São Paulo:
SARS-CoV 2
SARS Pneumonia
Tocilizumab
 Cytokine release syndrom
Interleukin-6
Hyperinflammation
Additional relevant MeSH terms:
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Pneumonia
Cytokine Release Syndrome
Respiratory Tract Infections
Infections
Lung Diseases
 Respiratory Tract Diseases
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock