Clinical trial NCT04445272: Clinical Trial to Evaluate the Effectiveness and Safety of Tocilizumab for Treating Patients With COVID-19 Pneumonia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Keywords: COVID-19
Lead sponsor: Fundacion SEIMC-GESIDA
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
name: Dynamic Science S.L.
First posted: 2020-06-24
Enrollment: 495
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Phase II, one-arm, open label, multicentre study
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: To calulate the time of intubation
timeFrame: through study completion, and average of 1 month
measure: To calculate the time with oxygen therapy
timeFrame: through study completion, and average of 1 month
measure: To calculate the time with Non-invasive mechanical ventilation
timeFrame: through study completion, and average of 1 month
measure: To evaluate mortality rate
timeFrame: through study completion, and average of 1 month
Secondary outcomes:
measure: To calculate respiratory function parameters
timeFrame: through study completion, and average of 1 month
measure: To calculate respiratory function parameters
timeFrame: through study completion, and average of 1 month
measure: To calculate respiratory function parameters
timeFrame: through study completion, and average of 1 month
measure: To evaluate radiological lung extension
timeFrame: through study completion, and average of 1 month
measure: To evaluate radiological evolution
timeFrame: through study completion, and average of 1 month
measure: To describe the duration of hospitalization and ICU use
timeFrame: through study completion, and average of 1 month
measure: To evaluate the requirement of additional organ support
timeFrame: through study completion, and average of 1 month
measure: To evaluate the requirement of additional organ support
timeFrame: through study completion, and average of 1 month
measure: To evaluate the requirement of additional organ support
timeFrame: through study completion, and average of 1 month
measure: To evaluate the requirement of additional organ support
timeFrame: through study completion, and average of 1 month
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory markers
timeFrame: through study completion, and average of 1 month
measure: To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab
timeFrame: through study completion, and average of 1 month
measure: To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab
timeFrame: through study completion, and average of 1 month
measure: To assess time to reverse-transcriptase polymerase chain reaction (RT-PCR) virus negativity
timeFrame: through study completion, and average of 1 month
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory
timeFrame: through study completion, and average of 1 month
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory
timeFrame: through study completion, and average of 1 month
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory
timeFrame: through study completion, and average of 1 month
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory
timeFrame: through study completion, and average of 1 month
measure: To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab
timeFrame: through study completion, and average of 1 month
measure: To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab
timeFrame: through study completion, and average of 1 month
measure: To calculate the number of adverse events of special interest in patients with COVID-19 pneumonia treated with Tocilizumab
timeFrame: through study completion, and average of 1 month
measure: To evaluate mortality rate
timeFrame: through study completion, and average of 1 month
measure: To evaluate respiratory function
timeFrame: through study completion, and average of 1 month
measure: To evaluate mortality rate
timeFrame: through study completion, and average of 1 month
measure: To evaluate mortality rate
timeFrame: through study completion, and average of 1 month
measure: To evaluate respiratory function
timeFrame: through study completion, and average of 1 month
measure: To evaluate respiratory function
timeFrame: through study completion, and average of 1 month
Other outcomes:
Locations:
city: Gijón
country: Spain
facility: Hospital Universitario de Cabueñes
state: Asturias
city: L'Hospitalet De Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
state: Barcelona
city: Manresa
country: Spain
facility: Hospital Sant Joan de Déu de Manresa
state: Barcelona
city: Mataró
country: Spain
facility: Hospital de Mataró
state: Barcelona
city: Galdakao
country: Spain
facility: Hospital Universitario de Galdakao
state: Bizkaia
city: Santander
country: Spain
facility: Hospital Universitario Marqués Valdecilla
state: Cantabria
city: Tomelloso
country: Spain
facility: Hospital Público General del Tomelloso
state: Ciudad Real
city: Jerez De La Frontera
country: Spain
facility: Hospital Jerez de la Frontera
state: Cádiz
city: Palma De Mallorca
country: Spain
facility: Hospital Universitari Son Espases
state: Islas Baleares
city: Alcorcón
country: Spain
facility: Hospital Universitario Fundación Alcorcón
state: Madrid
city: Fuenlabrada
country: Spain
facility: Hospital Universitario de Fuenlabrada
state: Madrid
city: Getafe
country: Spain
facility: Hospital Universitario de Getafe
state: Madrid
city: Móstoles
country: Spain
facility: Hospital Rey Juan Carlos
state: Madrid
city: Móstoles
country: Spain
facility: Hospital Universitario Rey Juan Carlos
state: Madrid
city: San Sebastián De Los Reyes
country: Spain
facility: Hospital Universitario Infanta Sofía
state: Madrid
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
state: Navarra
city: Talavera De La Reina
country: Spain
facility: Hospital Nuestra Señora del Prado
state: Toledo
city: Albacete
country: Spain
facility: Complejo Hospitalario Universitario de Albacete
city: Badajoz
country: Spain
facility: Hospital Infanta Cristina
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos
city: Gerona
country: Spain
facility: Hospital Universitario Dr. Josep Trueta
city: Granada
country: Spain
facility: Hospital Universitario Clínico San Cecilio
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Madrid
country: Spain
facility: Hospital Universitario Infanta Leonor
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Murcia
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Málaga
city: Orense
country: Spain
facility: Complexo Hospitalario Universitario de Ourense
city: Salamanca
country: Spain
facility: Hospital Universitario Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de la Macarena
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Toledo
country: Spain
facility: Hospital Virgen de la Salud
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Poliectenic La Fe
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Hospital Universitario Ramón y Cajal
name: Jose Antonio Pérez Molina
role: PRINCIPAL_INVESTIGATOR
References:
citation: Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014 Mar-Apr;20(2):119-22. doi: 10.1097/PPO.0000000000000035.