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

COVID Clinical Trial

— 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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04403685
• Other study ID #: TOCIBRAS
• Status: Terminated
• Phase: Phase 3
• Start date: May 8, 2020
• Est. completion date: July 21, 2020

Study information

• Verified date: August 2020
• Source: Beneficência Portuguesa de São Paulo
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 129
• Est. completion date: July 21, 2020
• Est. primary completion date: July 8, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• COVID
• Cytokine Release Syndrome
• Pneumonia
• SARS Pneumonia

Intervention

Drug:
• Tocilizumab
Single-dose infusion of 8 mg/kg. Maximum dose of 800 mg.

Locations

Country	Name	City	State
Brazil	Beneficência Portuguesa de Sao Paulo	Sao Paulo
Brazil	HAOC - Hospital Alemao Oswaldo Cruz	Sao Paulo
Brazil	HAOC - Hospital Alemao Oswaldo Cruz - unidade Vergueiro	Sao Paulo
Brazil	HCOR -Hospital do Coracao	Sao Paulo	SP
Brazil	HIAE - Hospital Israelita Albert Einstein	Sao Paulo
Brazil	HSL - Hospital Sírio Libanês	Sao Paulo
Brazil	UNIFESP	São Paulo	Sao Paulo

Sponsors (9)

Lead Sponsor	Collaborator
Beneficência Portuguesa de São Paulo	Brazilian Clinical Research Institute, Brazilian Research In Intensive Care Network, Federal University of São Paulo, Hospital Alemão Oswaldo Cruz, Hospital do Coracao, Hospital Israelita Albert Einstein, Hospital Moinhos de Vento, Hospital Sirio-Libanes

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Primary	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	All-cause mortality	All-cause mortality from randomization to day 28	29 days after the randomization
Secondary	Hospital Mortality	Deaths that occur during hospital admission.	29 days after the randomization
Secondary	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)
Secondary	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)
Secondary	Ventilator free days	Days alive and free from mechanical ventilation since randomization	29 days after the randomization
Secondary	Time until oxygen support independence	Days from randomization to independence of oxygen support	29 days after the randomization
Secondary	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
Secondary	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
Secondary	Duration of hospitalization	Lenght of hospitalization stay in survivors (in days)	29 days after the randomization
Secondary	Other infections	Incidence of other infections (aside from SARS-CoV 2)	29 days after the randomization
Secondary	Incidence of thromboembolic events	Incidence of thromboembolic events in patients with COVID-19	29 days after the randomization
Secondary	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)