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

Sponsor

Fundacion SEIMC-GESIDA (Other)

Overall Status

Completed

CT.gov ID

NCT04445272

Collaborator

Roche Pharma AG (Industry), Dynamic Science S.L. (Industry)

495

Enrollment

Locations

Arm

7.1

Actual Duration (Months)

11.8

Patients Per Site

1.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Tocilizumab	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

495 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Phase II, one-arm, open label, multicentre studyPhase II, one-arm, open label, multicentre study

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 22, 2020

Actual Primary Completion Date :

Dec 23, 2020

Actual Study Completion Date :

Dec 23, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tocilizumab 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 Treatment with Tocilizumab

Arm

Intervention/Treatment

Experimental: Tocilizumab

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

Treatment with Tocilizumab

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country
1	Hospital Universitario de Cabueñes	Gijón	Asturias	Spain
2	Hospital Universitari de Bellvitge	L'Hospitalet De Llobregat	Barcelona	Spain
3	Hospital Sant Joan de Déu de Manresa	Manresa	Barcelona	Spain
4	Hospital de Mataró	Mataró	Barcelona	Spain
5	Hospital Universitario de Galdakao	Galdakao	Bizkaia	Spain
6	Hospital Universitario Marqués Valdecilla	Santander	Cantabria	Spain
7	Hospital Público General del Tomelloso	Tomelloso	Ciudad Real	Spain
8	Hospital Jerez de la Frontera	Jerez De La Frontera	Cádiz	Spain
9	Hospital Universitari Son Espases	Palma De Mallorca	Islas Baleares	Spain
10	Hospital Universitario Fundación Alcorcón	Alcorcón	Madrid	Spain
11	Hospital Universitario de Fuenlabrada	Fuenlabrada	Madrid	Spain
12	Hospital Universitario de Getafe	Getafe	Madrid	Spain
13	Hospital Rey Juan Carlos	Móstoles	Madrid	Spain
14	Hospital Universitario Rey Juan Carlos	Móstoles	Madrid	Spain
15	Hospital Universitario Infanta Sofía	San Sebastián De Los Reyes	Madrid	Spain
16	Complejo Hospitalario de Navarra	Pamplona	Navarra	Spain
17	Hospital Nuestra Señora del Prado	Talavera De La Reina	Toledo	Spain
18	Complejo Hospitalario Universitario de Albacete	Albacete		Spain
19	Hospital Infanta Cristina	Badajoz		Spain
20	Hospital Clínic i Provincial Barcelona	Barcelona		Spain
21	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain
22	Hospital Universitario de Burgos	Burgos		Spain
23	Hospital Universitario Dr. Josep Trueta	Gerona		Spain
24	Hospital Universitario Clínico San Cecilio	Granada		Spain
25	Hospital Universitario Virgen de las Nieves	Granada		Spain
26	Hospital General Universitario Gregorio Marañón	Madrid		Spain
27	Hospital Universitario Fundación Jiménez Díaz	Madrid		Spain
28	Hospital Universitario HM Sanchinarro	Madrid		Spain
29	Hospital Universitario Infanta Leonor	Madrid		Spain
30	Hospital Universitario Ramón y Cajal	Madrid		Spain
31	Hospital Clínico Universitario Virgen de la Arrixaca	Murcia		Spain
32	Hospital Regional Universitario de Málaga	Málaga		Spain
33	Complexo Hospitalario Universitario de Ourense	Orense		Spain
34	Hospital Universitario Salamanca	Salamanca		Spain
35	Hospital Universitario Virgen de la Macarena	Sevilla		Spain
36	Hospital Universitario Virgen del Rocío	Sevilla		Spain
37	Hospital Virgen de la Salud	Toledo		Spain
38	Hospital Clinico Universitario de Valencia	Valencia		Spain
39	Hospital Universitari i Poliectenic La Fe	Valencia		Spain
40	Hospital Universitario Dr. Peset	Valencia		Spain
41	Hospital Clínico Universitario Lozano Blesa	Zaragoza		Spain
42	Hospital Universitario Miguel Servet	Zaragoza		Spain

Sponsors and Collaborators

Fundacion SEIMC-GESIDA
Roche Pharma AG
Dynamic Science S.L.

Investigators

Principal Investigator: Jose Antonio Pérez Molina, Hospital Universitario Ramón y Cajal

Study Documents (Full-Text)

None provided.

More Information

Publications

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. Review.

Responsible Party:

Fundacion SEIMC-GESIDA

ClinicalTrials.gov Identifier:

NCT04445272

Other Study ID Numbers:

BREATH-19 (FSG011-20)

First Posted:

Jun 24, 2020

Last Update Posted:

Jun 2, 2021

Last Verified:

Jun 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Fundacion SEIMC-GESIDA

COVID-19

Additional relevant MeSH terms:

COVID-19

Pneumonia

Study Results

No Results Posted as of Jun 2, 2021