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

Phase 3

Terminated

• Conditions: Cytokine Release Syndrome; COVID; SARS Pneumonia
• Interventions: Drug: Tocilizumab

• Registration Number: NCT04403685
• Lead Sponsor: Beneficência Portuguesa de São Paulo

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.

Study Timeline

• Study Start: 2020-05-08
• Study First Submitted: 2020-05-24
• Study First Submitted QC: 2020-05-24
• Study First Posted: 2020-05-27
• Primary Completion: 2020-07-08
• Study Completion: 2020-07-21
• Status Verified: 2020-08
• Last Update Submitted: 2020-08-22
• Last Update Posted: 2020-08-26

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 129

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tocilizumab	Tocilizumab	Single-dose tocilizumab of 8 mg/kg (maximum dose of 800mg). Best supportive care.

Primary Outcome Measures

Name	Time	Method
Evaluation of clinical status	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

Name	Time	Method
Time until oxygen support independence	29 days after the randomization	Days from randomization to independence of oxygen support
Incidence of adverse events	29 days after the randomization (specific evaluations at D8, D15 and D29)	Evaluation of adverse events, as well as serious and unexpected adverse events
Hospital Mortality	29 days after the randomization	Deaths that occur during hospital admission.
Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale	29 days after the randomization (evaluations at D8 and D15)	Improvement of SOFA scale of patients at day 8, 15 and 29 after randomization
Evaluation of clinical status	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)
Need of mechanical ventilation support	29 days after the randomization	Number of patients that were not at mechanical ventilation at randomization and that required that support.
Duration of hospitalization	29 days after the randomization	Lenght of hospitalization stay in survivors (in days)
All-cause mortality	29 days after the randomization	All-cause mortality from randomization to day 28
Ventilator free days	29 days after the randomization	Days alive and free from mechanical ventilation since randomization
Days to mechanical ventilation support.	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.
Other infections	29 days after the randomization	Incidence of other infections (aside from SARS-CoV 2)
Incidence of thromboembolic events	29 days after the randomization	Incidence of thromboembolic events in patients with COVID-19

Trial Locations

Locations (7)

HCOR -Hospital do Coracao; 🇧🇷 Sao Paulo, SP, Brazil

Beneficência Portuguesa de Sao Paulo; 🇧🇷 Sao Paulo, Brazil

UNIFESP; 🇧🇷 São Paulo, Sao Paulo, Brazil

HAOC - Hospital Alemao Oswaldo Cruz; 🇧🇷 Sao Paulo, Brazil

HIAE - Hospital Israelita Albert Einstein; 🇧🇷 Sao Paulo, Brazil

HAOC - Hospital Alemao Oswaldo Cruz - unidade Vergueiro; 🇧🇷 Sao Paulo, Brazil

HSL - Hospital Sírio Libanês; 🇧🇷 Sao Paulo, Brazil