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

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)

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.

Study Overview

• Status: Terminated
• Conditions: COVID; Cytokine Release Syndrome; SARS Pneumonia
• Intervention / Treatment: Drug: Tocilizumab

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 Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil, 01323001
    • HAOC - Hospital Alemão Oswaldo Cruz
  • Sao Paulo, Brazil, 01323900
    • Beneficência Portuguesa de São Paulo
  • Sao Paulo, Brazil
    • HAOC - Hospital Alemao Oswaldo Cruz - unidade Vergueiro
  • Sao Paulo, Brazil
    • HIAE - Hospital Israelita Albert Einstein
  • Sao Paulo, Brazil
    • HSL - Hospital Sírio Libanês
  • SP
    • Sao Paulo, SP, Brazil, 04004030
      • HCOR -Hospital do Coracao
  • Sao Paulo
    • São Paulo, Sao Paulo, Brazil
      • UNIFESP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: Actemra
No Intervention: Control arm; Best supportive care.

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of inflammatory tests and cytokines with clinical outcomes	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	29 days after the randomization
Exploratory evaluation of laboratory exams during hospitalization	Evaluation the kinetics of hemostasia exams, inflammatory tests, cytokines, flow cytometry of blood cells, CBC, renal and liver exams	29 days after the randomization
Evaluation of viral clearance of SARS-CoV2	Evaluation of viral clearance of SARS-CoV2 using RT-PCR analysis of nasopharyngeal swab	Day 8 and 15 after randomization

Collaborators and Investigators

• Sponsor: Beneficência Portuguesa de São Paulo
• Collaborators: Federal University of São Paulo; Hospital Israelita Albert Einstein; Hospital Moinhos de Vento; Brazilian Clinical Research Institute; Hospital do Coracao; Hospital Sirio-Libanes; Hospital Alemão Oswaldo Cruz; Brazilian Research In Intensive Care Network
• Investigators: Principal Investigator: Viviane C Veiga, MD, Beneficência Portuguesa de São Paulo

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2020
• Primary Completion (Actual): July 8, 2020
• Study Completion (Actual): July 21, 2020

Study Registration Dates

• First Submitted: May 24, 2020
• First Submitted That Met QC Criteria: May 24, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Actual): August 26, 2020
• Last Update Submitted That Met QC Criteria: August 22, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Tocilizumab; SARS-CoV 2; Interleukin-6; SARS Pneumonia; Cytokine release syndrom; Hyperinflammation
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pneumonia; Cytokine Release Syndrome
• Other Study ID Numbers: TOCIBRAS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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