Clinical Trial to Evaluate the Effectiveness and Safety of Tocilizumab for Treating Patients With COVID-19 Pneumonia

Study Overview
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Brief Summary
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At present, no treatment has been approved for COVID-19. However, in light of the increased interest on using the anti-cytokine therapy targeting IL-6 tocilizumab in COVID-19 infected patients due to its potential benefit, the Spanish Agency for Medicine and Health Products (Agencia Española de Medicamentos y Productos Sanitarios, AEMPS) have initiated the controlled distribution of the drug. Tocilizumab is indeed proposed as a potential treatment for severe COVID-19 in Spain. Based on the positive results of tocilizumab in the treatment of COVID-19 patients and the experience of tocilizumab in inducing rapid reversal of CSS in other pathologies several clinical trials and observational studies are being conducted to assess the effectiveness and safety of tocilizumab in COVID-19 patients. Further studies with a large sample size are required to confirm the effectiveness of tocilizumab in patients with COVID-19 pneumonia. The need for the management of severe COVID-19 disease is imperative, and every effort should be made to collect relevant clinical outcomes. The aim of the present study is to evaluate the effectiveness of IV tocilizumab in treating patients with COVID-19 pneumonia who are currently hospitalized or admitted to ICU by describing improvement of respiratory function and mortality rate. This large real-world cohort therefore provides a unique opportunity to study this potential medicine during the current emergency situation, and support the findings from other ongoing clinical trials and observational studies, such as the Roche-sponsored Phase III study that is planned to start early April.

Detailed Description
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Cytokine storm syndrome (CSS) is caused by the excessive release of cytokines during an exaggerated immune response. CSS can be triggered by infections or therapeutic interventions, being more severe depending on the degree and duration of immune activation. CSS is as a significant on-target side-effect of chimeric antigen receptor (CAR) T-cell therapies, which have been subject to assessment for the treatment of haematological malignancies. Tocilizumab (intravenous, IV) is indicated for the treatment of chimeric antigen receptor CAR T cell-induced severe or life-threatening CSS. Based on the experience with tocilizumab in the CSS, and that some patients infected with SARS-CoV-2 can develop CSS, leading to potentially fatal damage to lung tissue, the drug is being investigated in China and Italy, and clinical trials are being conducted/planned in these and several other countries. Real-word experience with tocilizumab IV have shown that in a substantial proportion of COVID-19 patients with severe pneumonia, fever returned to normal and respiratory function based on oxygen intake and lung opacities improved remarkably. Laboratory parameters such as C-reactive protein (CRP) that seem to be increased in patients infected decreased significantly with tocilizumab, and lymphocytes levels also returned to normal. All these findings have led the Spanish Agency for Medicine and Health Products (AEMPS) to initiate the controlled distribution of tocilizumab IV, in light of the increased interest on the anti-cytokine therapy targeting IL-6 in COVID-19 infected patients. Therefore, tocilizumab might be among the therapeutic armamentarium for preventing the fatal consequences of acute respiratory and multi organ failure in around 20% of the COVID-19 infected patients. The aim of the present study is to evaluate the effectiveness and safety of IV tocilizumab in patients with COVID-19 severe pneumonia who are currently hospitalized or admitted to ICU. This large real-world cohort provides a unique opportunity to study a potential medicine during the current emergency situation, and support the findings from the Roche-sponsored Phase III study that is planned to start in early April.

Official Title
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A Multicentre, Open-label Clinical Trial to Evaluate the Effectiveness and Safety of Intravenous Tocilizumab for Treating Patients With COVID-19 Pneumonia: the BREATH-19 Study

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide oral informed consent to participate in this study. At least 18 years of age. Diagnosed with COVID-19 pneumonia by RT-PCR. Have received the first dose of tocilizumab a maximum of two days before the inclusion or is candidate for tocilizumab treatment Hospitalized or admitted to ICU Exclusion Criteria: The patient has any other medical condition or is receiving concomitant medication that could, in the opinion of the investigator, compromise the patient's safety or collected data Known severe allergic reactions to tocilizumab or other monoclonal antibodies Active acute and severe infections, including tuberculosis infection Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Phase II, one-arm, open label, multicentre study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab<br>Patients will receive IV tocilizumab as per clinical practice and at the discretion of treating investigator, following the posology indicated in the SmPC, or the recommendations proposed by the Spanish Ministry of Health: The recommended posology by the SmPC is 8 mg per kg in patients weighing greater than or equal to 30 kg or 12 mg per kg in patients weighing less than 30 kg. If no clinical improvement in the signs and symptoms up to 3 additional doses of tocilizumab may be administered. The interval between consecutive doses should be at least 8 hours. The recommendations of the Spanish Ministry of Health: Patients more than 80 kg: first dose 600 mg; second dose 600 mg. Patients less than 80 kg: first dose 600 mg; second dose 400 mg. A third dose might be considered 16 to 24 hours after if: fever persists or a worsening of the laboratory parameters Given the exceptionality of the situation modification of doses according to the physician experience will be allowed. | Drug: Tocilizumab<br>* Treatment with Tocilizumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To calulate the time of intubation | Calculate the mean time of intubation | through study completion, and average of 1 month | 
| To calculate the time with oxygen therapy | Calculate the mean time with oxygen therapy | through study completion, and average of 1 month | 
| To calculate the time with Non-invasive mechanical ventilation | Calculate the mean time with Non-invasive mechanical ventilation | through study completion, and average of 1 month | 
| To evaluate mortality rate | Number of patients deaths of the total of patients included | through study completion, and average of 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To calculate respiratory function parameters | To calculate the mean ofPaO2/FiO2 | through study completion, and average of 1 month | 
| To calculate respiratory function parameters | To calculate the mean of levels of oxygen saturation | through study completion, and average of 1 month | 
| To calculate respiratory function parameters | To calculate the mean of SaO2/FiO2 | through study completion, and average of 1 month | 
| To evaluate radiological lung extension | Evaluate the lung extension of pneumonia | through study completion, and average of 1 month | 
| To evaluate radiological evolution | Evaluate the type of lung affection | through study completion, and average of 1 month | 
| To describe the duration of hospitalization and ICU use | Days of hospitalization in survivors and/or days at ICU throughout the study | through study completion, and average of 1 month | 
| To evaluate the requirement of additional organ support | Percentage of patients with extracorporeal membrane oxygenation | through study completion, and average of 1 month | 
| To evaluate the requirement of additional organ support | Percentage of patients with molecular adsorbent recirculating system | through study completion, and average of 1 month | 
| To evaluate the requirement of additional organ support | Percentage of patients with dialysis | through study completion, and average of 1 month | 
| To evaluate the requirement of additional organ support | Percentage of patients with other support therapy | through study completion, and average of 1 month | 
| To evaluate the effect of IV tocilizumab on the serum levels of inflammatory markers | Analyze the levels of IL-6 | through study completion, and average of 1 month | 
| To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab | Incidence of adverse events | through study completion, and average of 1 month | 
| To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab | Incidence of adverse events by dose of Tocilizumab | through study completion, and average of 1 month | 
| To assess time to reverse-transcriptase polymerase chain reaction (RT-PCR) virus negativity | To evaluate the time to RT-PCR virus negativity | through study completion, and average of 1 month | 
| To evaluate the effect of IV tocilizumab on the serum levels of inflammatory | Analyze the levels of CRP | through study completion, and average of 1 month | 
| To evaluate the effect of IV tocilizumab on the serum levels of inflammatory | Analyze the levels of procalcitonin (PCT) | through study completion, and average of 1 month | 
| To evaluate the effect of IV tocilizumab on the serum levels of inflammatory | Analyze the levels of ID-dimer | through study completion, and average of 1 month | 
| To evaluate the effect of IV tocilizumab on the serum levels of inflammatory | Analyze the levels of ferritin | through study completion, and average of 1 month | 
| To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab | Indicende of serious adverse events | through study completion, and average of 1 month | 
| To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab | Indicende of serious adverse events based on dose of Tocilizumab | through study completion, and average of 1 month | 
| To calculate the number of adverse events of special interest in patients with COVID-19 pneumonia treated with Tocilizumab | Indicende of adverse events of special interest based on dose of Tocilizumab | through study completion, and average of 1 month | 
| To evaluate mortality rate | Number of patients deaths of the total of patients included based on dose of Tocilizumab | through study completion, and average of 1 month | 
| To evaluate respiratory function | Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on dose of Tocilizumab | through study completion, and average of 1 month | 
| To evaluate mortality rate | Number of patients deaths of the total of patients included based on severity of disease at the start of the study treatment | through study completion, and average of 1 month | 
| To evaluate mortality rate | Number of patients deaths of the total of patients included based on presence of cytokine storm syndrome at the start of treatment | through study completion, and average of 1 month | 
| To evaluate respiratory function | Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on severity of disease at the start of the study treatment | through study completion, and average of 1 month | 
| To evaluate respiratory function | Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on presence of cytokine storm syndrome at the start of treatment | through study completion, and average of 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19