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Tocilizumab Versus Methylprednisolone in the Cytokine Release Syndrome of Patients With COVID-19

Primary Purpose

Cytokine Release Syndrome, Covid-19

Status
Terminated
Phase
Phase 2
Locations
Brazil
Study Type
Interventional
Intervention
Tocilizumab 180 MG/ML
Methylprednisolone Sodium Succinate
Sponsored by
Hospital Sao Domingos
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cytokine Release Syndrome focused on measuring Cytokine release syndrome, COVID-19, Tocilizumab, Methylprednisolone, Safety, Efficacy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Men and non-pregnant women over 18 years old COVID diagnosis confirmed by real time polymerase chain reaction (RT-PCR) Pao2 / FIO2 <200 Laboratory: high sensitivity C reactive protein> 5 mg / L; lactic dehydrogenase (LDH ) > 245 U / l; Ferritin> 300; D-dimer> 1500; Interleukin-6> 7.0 pg / ml.

Exclusion Criteria:

  • Known sensitivity/Allergy to tocilizumab
  • Active tuberculosis
  • Pregnancy
  • Individuals, in the opinion of the investigators where progression to death is imminent and inevitable in the next 24 hours

Sites / Locations

  • Hospital Sao Domingos

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Tocilizumab

Methylprednisolone

Arm Description

Patients will receive Tocilizumab, 8 mg / kg diluted in 100 ml of saline and administered IV for 60 minutes. The dose will be repeated only once 12 hours after the first dose.

Patients will receive methylprednisolone at a dose of 1.5 mg / kg / day divided into 2 daily doses for 7 days. Then they will receive 1 mg / kg / day for another 7 days in two daily doses. Finally 0.5 mg / kg / day for another 7 days.

Outcomes

Primary Outcome Measures

Patient clinical status 15 days after randomization
A seven-category ordinal scale consisting of: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.

Secondary Outcome Measures

Improving oxygenation
Improvement in PaO2/FIO2
Thorax CT improvement
Improvement in the computed tomography between D0 and D10 after randomization
ICU length of stay
Duration o ICU stay in days
Duration of mechanical ventilation
Days of mechanical ventilation
Incidence of acute kidney (AKI) with necessity of renal replacement therapy
AKI according to Kidney Disease Improving Global Outcomes (KDIGO)

Full Information

First Posted
May 2, 2020
Last Updated
March 14, 2022
Sponsor
Hospital Sao Domingos
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1. Study Identification

Unique Protocol Identification Number
NCT04377503
Brief Title
Tocilizumab Versus Methylprednisolone in the Cytokine Release Syndrome of Patients With COVID-19
Official Title
Comparison of the Efficacy and Safety of Tocilizumab Versus Methylprednisolone in the Cytokine Release Syndrome of Patients With COVID-19. A Prospective Randomized Controlled Phase II Trial
Study Type
Interventional

2. Study Status

Record Verification Date
May 2020
Overall Recruitment Status
Terminated
Why Stopped
The number of critically ill patients wirh COVID-19 decrease abruptly
Study Start Date
May 1, 2020 (Actual)
Primary Completion Date
August 31, 2020 (Actual)
Study Completion Date
November 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Hospital Sao Domingos

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study compare the efficacy and safety of tocilizumab versus methylprednisolone in the cytokine release syndrome of patients with COVID-19
Detailed Description
In December 2019, several patients were diagnosed with pneumonia of undefined etiology in Wuhan, China. A few days later, a virus was identified as the etiologic agent. It was a new beta coronavirus that received the name of Severe Acute Respiratory Syndrome Coroinavirus (SARS-COV-2). The disease quickly spread to the Wuhan region and in March reached northern Italy and soon across Europe. On March 14, the World Health Organization declared that COVID-19 had acquired seriousness and spread to be defined as a pandemic. Since then, COVID-19 has challenged the ability of rich countries to meet the demand for beds, especially ICU beds, and it has also challenged science in search of effective treatment, while in record time research centers begins testing with a vaccine. Although a significant percentage of patients with COVID-19 have a benign evolution, around 20% of cases the disease acquires sufficient severity from the point of view of lung involvement to justify treatment in the ICU. In addition, around 5% of patients evolve with extremely serious forms and are associated with a lethality of up to 60%. Some of these patients demonstrated in studies alterations in cellular and humoral immunity compatible with the cytokine release syndrome, an entity that has been described complicating the use of antineoplastic drugs and viral infections. At this moment several studies, some of them with conclusions already seek to identify effective forms of treatment. Antiviral drugs such as Lopinavir-Ritonavir, which has already been tested in a prospective randomized study and has not been shown to be effective. The antiviral rendecivir was tested in a preliminary study brought a positive expectation and the hydroxychloroquine in studies with small samples is the drug that currently meets the highest expectations. None of these drugs, however, is effective in the case of the group of patients who acquire severity as a result of what has been called a cytokine storm. In this case, expectations are turned to interleukin antagonists and corticosteroids. Among the interleukin antagonists the drug that meets the most expectations is Tocilizumab, an interleukin-6 antagonist that has proven efficacy in the cytokine release syndrome caused by antineoplastic drugs. There are currently ongoing studies analyzing the role of tocilizumab and, at the same time, and along the same line, corticosteroids are being tested. There is currently no prospective randomized study examining the role of tocilizumab. Regarding corticosteroids, the only evidence comes from a retrospective study involving 201 patients with COVID pneumonia 19 and acute respiratory distress syndrome. This study showed an association between corticosteroids and reduced risk of death (HR 0.38; p = 0.003).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cytokine Release Syndrome, Covid-19
Keywords
Cytokine release syndrome, COVID-19, Tocilizumab, Methylprednisolone, Safety, Efficacy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Model Description
Prospective randomized controlled phase 2 study
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tocilizumab
Arm Type
Experimental
Arm Description
Patients will receive Tocilizumab, 8 mg / kg diluted in 100 ml of saline and administered IV for 60 minutes. The dose will be repeated only once 12 hours after the first dose.
Arm Title
Methylprednisolone
Arm Type
Active Comparator
Arm Description
Patients will receive methylprednisolone at a dose of 1.5 mg / kg / day divided into 2 daily doses for 7 days. Then they will receive 1 mg / kg / day for another 7 days in two daily doses. Finally 0.5 mg / kg / day for another 7 days.
Intervention Type
Drug
Intervention Name(s)
Tocilizumab 180 MG/ML
Intervention Description
Tocilizumab 8 mg/kg diluted in 100 ml of saline administered in 60 minutes. The dose will be repeated after 12 hours.
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone Sodium Succinate
Intervention Description
Patients will receive methylprednisolone at a dose of 1.5 mg / kg / day divided into 2 daily doses for 7 days. Then they will receive 1 mg / kg / day for another 7 days. Finally 0.5 mg / kg / day until 21 days of use
Primary Outcome Measure Information:
Title
Patient clinical status 15 days after randomization
Description
A seven-category ordinal scale consisting of: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
Time Frame
15 days after randomization
Secondary Outcome Measure Information:
Title
Improving oxygenation
Description
Improvement in PaO2/FIO2
Time Frame
15 days
Title
Thorax CT improvement
Description
Improvement in the computed tomography between D0 and D10 after randomization
Time Frame
10 days
Title
ICU length of stay
Description
Duration o ICU stay in days
Time Frame
28 days
Title
Duration of mechanical ventilation
Description
Days of mechanical ventilation
Time Frame
28 days
Title
Incidence of acute kidney (AKI) with necessity of renal replacement therapy
Description
AKI according to Kidney Disease Improving Global Outcomes (KDIGO)
Time Frame
15 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and non-pregnant women over 18 years old COVID diagnosis confirmed by real time polymerase chain reaction (RT-PCR) Pao2 / FIO2 <200 Laboratory: high sensitivity C reactive protein> 5 mg / L; lactic dehydrogenase (LDH ) > 245 U / l; Ferritin> 300; D-dimer> 1500; Interleukin-6> 7.0 pg / ml. Exclusion Criteria: Known sensitivity/Allergy to tocilizumab Active tuberculosis Pregnancy Individuals, in the opinion of the investigators where progression to death is imminent and inevitable in the next 24 hours
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
PEDRO B FROTA, MD
Organizational Affiliation
Hospital Sao Domingos
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Sao Domingos
City
Sao Luis
State/Province
MA
ZIP/Postal Code
65060-000
Country
Brazil

12. IPD Sharing Statement

Plan to Share IPD
No
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Tocilizumab Versus Methylprednisolone in the Cytokine Release Syndrome of Patients With COVID-19

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