Clinical trial NCT04403685: Safety and Efficacy of Tocilizumab in Moderate to Severe COVID-19 With Inflammatory Markers
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
Overall status: TERMINATED
Phase: PHASE3
Conditions: COVID
SARS Pneumonia
Cytokine Release Syndrome
Keywords: SARS-CoV 2
SARS Pneumonia
Tocilizumab
Cytokine release syndrom
Interleukin-6
Hyperinflammation
Lead sponsor: Beneficência Portuguesa de São Paulo
Sponsor class: OTHER
Collaborators: name: Hospital do Coracao
name: Hospital Israelita Albert Einstein
name: Hospital Sirio-Libanes
name: Hospital Alemão Oswaldo Cruz
name: Brazilian Research In Intensive Care Network
name: Hospital Moinhos de Vento
name: Brazilian Clinical Research Institute
name: Federal University of São Paulo
First posted: 2020-05-27
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized, superiority, open-label, controlled trial. Randomization 1:1 to best supportive care (BSC) versus Tocilizumab + BSC
Primary purpose: TREATMENT

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.

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

  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

Primary outcomes:
measure: Evaluation of clinical status
timeFrame: Day 15 of the trial
Secondary outcomes:
measure: All-cause mortality
timeFrame: 29 days after the randomization
measure: Hospital Mortality
timeFrame: 29 days after the randomization
measure: Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale
timeFrame: 29 days after the randomization (evaluations at D8 and D15)
measure: Evaluation of clinical status
timeFrame: 29 days after the randomization (evaluations at D8 and D29)
measure: Ventilator free days
timeFrame: 29 days after the randomization
measure: Time until oxygen support independence
timeFrame: 29 days after the randomization
measure: Need of mechanical ventilation support
timeFrame: 29 days after the randomization
measure: Days to mechanical ventilation support.
timeFrame: 29 days after the randomization
measure: Duration of hospitalization
timeFrame: 29 days after the randomization
measure: Other infections
timeFrame: 29 days after the randomization
measure: Incidence of thromboembolic events
timeFrame: 29 days after the randomization
measure: Incidence of adverse events
timeFrame: 29 days after the randomization (specific evaluations at D8, D15 and D29)
Other outcomes:
measure: Correlation of inflammatory tests and cytokines with clinical outcomes
timeFrame: 29 days after the randomization
measure: Exploratory evaluation of laboratory exams during hospitalization
timeFrame: 29 days after the randomization
measure: Evaluation of viral clearance of SARS-CoV2
timeFrame: Day 8 and 15 after randomization
Locations:
city: São Paulo
country: Brazil
facility: UNIFESP
state: Sao Paulo
city: Sao Paulo
country: Brazil
facility: HCOR -Hospital do Coracao
state: SP
city: Sao Paulo
country: Brazil
facility: HAOC - Hospital Alemao Oswaldo Cruz
city: Sao Paulo
country: Brazil
facility: Beneficência Portuguesa de Sao Paulo
city: Sao Paulo
country: Brazil
facility: HAOC - Hospital Alemao Oswaldo Cruz - unidade Vergueiro
city: Sao Paulo
country: Brazil
facility: HIAE - Hospital Israelita Albert Einstein
city: Sao Paulo
country: Brazil
facility: HSL - Hospital Sírio Libanês
Study officials:
affiliation: Beneficência Portuguesa de Sao Paulo
name: Viviane C Veiga, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.