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Tocilizumab Versus Methylprednisolone in the Cytokine Release Syndrome of Patients With COVID-19

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ClinicalTrials.gov Identifier: NCT04377503
Recruitment Status : Not yet recruiting
First Posted : May 6, 2020
Last Update Posted : May 6, 2020
Sponsor:
Information provided by (Responsible Party):
José Raimundo Araujo de Azevedo, Hospital Sao Domingos

Brief Summary:
This study compare the efficacy and safety of tocilizumab versus methylprednisolone in the cytokine release syndrome of patients with COVID-19

Condition or disease Intervention/treatment Phase
Cytokine Release Syndrome Covid-19 Drug: Tocilizumab 180 MG/ML Drug: Methylprednisolone Sodium Succinate Phase 2

Detailed Description:

In December 2019, several patients were diagnosed with pneumonia of undefined etiology in Wuhan, China. A few days later, a virus was identified as the etiologic agent. It was a new beta coronavirus that received the name of Severe Acute Respiratory Syndrome Coroinavirus (SARS-COV-2).

The disease quickly spread to the Wuhan region and in March reached northern Italy and soon across Europe. On March 14, the World Health Organization declared that COVID-19 had acquired seriousness and spread to be defined as a pandemic.

Since then, COVID-19 has challenged the ability of rich countries to meet the demand for beds, especially ICU beds, and it has also challenged science in search of effective treatment, while in record time research centers begins testing with a vaccine.

Although a significant percentage of patients with COVID-19 have a benign evolution, around 20% of cases the disease acquires sufficient severity from the point of view of lung involvement to justify treatment in the ICU. In addition, around 5% of patients evolve with extremely serious forms and are associated with a lethality of up to 60%. Some of these patients demonstrated in studies alterations in cellular and humoral immunity compatible with the cytokine release syndrome, an entity that has been described complicating the use of antineoplastic drugs and viral infections.

At this moment several studies, some of them with conclusions already seek to identify effective forms of treatment. Antiviral drugs such as Lopinavir-Ritonavir, which has already been tested in a prospective randomized study and has not been shown to be effective. The antiviral rendecivir was tested in a preliminary study brought a positive expectation and the hydroxychloroquine in studies with small samples is the drug that currently meets the highest expectations. None of these drugs, however, is effective in the case of the group of patients who acquire severity as a result of what has been called a cytokine storm. In this case, expectations are turned to interleukin antagonists and corticosteroids. Among the interleukin antagonists the drug that meets the most expectations is Tocilizumab, an interleukin-6 antagonist that has proven efficacy in the cytokine release syndrome caused by antineoplastic drugs. There are currently ongoing studies analyzing the role of tocilizumab and, at the same time, and along the same line, corticosteroids are being tested. There is currently no prospective randomized study examining the role of tocilizumab. Regarding corticosteroids, the only evidence comes from a retrospective study involving 201 patients with COVID pneumonia 19 and acute respiratory distress syndrome. This study showed an association between corticosteroids and reduced risk of death (HR 0.38; p = 0.003).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Prospective randomized controlled phase 2 study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Comparison of the Efficacy and Safety of Tocilizumab Versus Methylprednisolone in the Cytokine Release Syndrome of Patients With COVID-19. A Prospective Randomized Controlled Phase II Trial
Estimated Study Start Date : May 2020
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : November 2020


Arm Intervention/treatment
Experimental: Tocilizumab
Patients will receive Tocilizumab, 8 mg / kg diluted in 100 ml of saline and administered IV for 60 minutes. The dose will be repeated only once 12 hours after the first dose.
Drug: Tocilizumab 180 MG/ML
Tocilizumab 8 mg/kg diluted in 100 ml of saline administered in 60 minutes. The dose will be repeated after 12 hours.

Drug: Methylprednisolone Sodium Succinate
Patients will receive methylprednisolone at a dose of 1.5 mg / kg / day divided into 2 daily doses for 7 days. Then they will receive 1 mg / kg / day for another 7 days. Finally 0.5 mg / kg / day until 21 days of use

Active Comparator: Methylprednisolone
Patients will receive methylprednisolone at a dose of 1.5 mg / kg / day divided into 2 daily doses for 7 days. Then they will receive 1 mg / kg / day for another 7 days in two daily doses. Finally 0.5 mg / kg / day for another 7 days.
Drug: Tocilizumab 180 MG/ML
Tocilizumab 8 mg/kg diluted in 100 ml of saline administered in 60 minutes. The dose will be repeated after 12 hours.

Drug: Methylprednisolone Sodium Succinate
Patients will receive methylprednisolone at a dose of 1.5 mg / kg / day divided into 2 daily doses for 7 days. Then they will receive 1 mg / kg / day for another 7 days. Finally 0.5 mg / kg / day until 21 days of use




Primary Outcome Measures :
  1. Patient clinical status 15 days after randomization [ Time Frame: 15 days after randomization ]
    A seven-category ordinal scale consisting of: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.


Secondary Outcome Measures :
  1. Improving oxygenation [ Time Frame: 15 days ]
    Improvement in PaO2/FIO2

  2. Thorax CT improvement [ Time Frame: 10 days ]
    Improvement in the computed tomography between D0 and D10 after randomization

  3. ICU length of stay [ Time Frame: 28 days ]
    Duration o ICU stay in days

  4. Duration of mechanical ventilation [ Time Frame: 28 days ]
    Days of mechanical ventilation

  5. Incidence of acute kidney (AKI) with necessity of renal replacement therapy [ Time Frame: 15 days ]
    AKI according to Kidney Disease Improving Global Outcomes (KDIGO)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Men and non-pregnant women over 18 years old COVID diagnosis confirmed by real time polymerase chain reaction (RT-PCR) Pao2 / FIO2 <200 Laboratory: high sensitivity C reactive protein> 5 mg / L; lactic dehydrogenase (LDH ) > 245 U / l; Ferritin> 300; D-dimer> 1500; Interleukin-6> 7.0 pg / ml.

Exclusion Criteria:

  • Known sensitivity/Allergy to tocilizumab
  • Active tuberculosis
  • Pregnancy
  • Individuals, in the opinion of the investigators where progression to death is imminent and inevitable in the next 24 hours

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04377503


Contacts
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Contact: JOSE A AZEVEDO, MD, PhD +559832168110 jrazevedo47@gmail.com
Contact: HUGO C LIMA, MD +559832168110 hugolima49@gmail.com

Sponsors and Collaborators
Hospital Sao Domingos
Investigators
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Principal Investigator: PEDRO B FROTA, MD Hospital Sao Domingos
Publications:
Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, Cereda D, Coluccello A, Foti G, Fumagalli R, Iotti G, Latronico N, Lorini L, Merler S, Natalini G, Piatti A, Ranieri MV, Scandroglio AM, Storti E, Cecconi M, Pesenti A; COVID-19 Lombardy ICU Network, Nailescu A, Corona A, Zangrillo A, Protti A, Albertin A, Forastieri Molinari A, Lombardo A, Pezzi A, Benini A, Scandroglio AM, Malara A, Castelli A, Coluccello A, Micucci A, Pesenti A, Sala A, Alborghetti A, Antonini B, Capra C, Troiano C, Roscitano C, Radrizzani D, Chiumello D, Coppini D, Guzzon D, Costantini E, Malpetti E, Zoia E, Catena E, Agosteo E, Barbara E, Beretta E, Boselli E, Storti E, Harizay F, Della Mura F, Lorini FL, Donato Sigurtà F, Marino F, Mojoli F, Rasulo F, Grasselli G, Casella G, De Filippi G, Castelli G, Aldegheri G, Gallioli G, Lotti G, Albano G, Landoni G, Marino G, Vitale G, Battista Perego G, Evasi G, Citerio G, Foti G, Natalini G, Merli G, Sforzini I, Bianciardi L, Carnevale L, Grazioli L, Cabrini L, Guatteri L, Salvi L, Dei Poli M, Galletti M, Gemma M, Ranucci M, Riccio M, Borelli M, Zambon M, Subert M, Cecconi M, Mazzoni MG, Raimondi M, Panigada M, Belliato M, Bronzini N, Latronico N, Petrucci N, Belgiorno N, Tagliabue P, Cortellazzi P, Gnesin P, Grosso P, Gritti P, Perazzo P, Severgnini P, Ruggeri P, Sebastiano P, Covello RD, Fernandez-Olmos R, Fumagalli R, Keim R, Rona R, Valsecchi R, Cattaneo S, Colombo S, Cirri S, Bonazzi S, Greco S, Muttini S, Langer T, Alaimo V, Viola U. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6. doi: 10.1001/jama.2020.5394. [Epub ahead of print]

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Responsible Party: José Raimundo Araujo de Azevedo, Principal investigator, Hospital Sao Domingos
ClinicalTrials.gov Identifier: NCT04377503    
Other Study ID Numbers: covid-19 hsd
First Posted: May 6, 2020    Key Record Dates
Last Update Posted: May 6, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by José Raimundo Araujo de Azevedo, Hospital Sao Domingos:
Cytokine release syndrome
COVID-19
Tocilizumab
Methylprednisolone
Safety
Efficacy
Additional relevant MeSH terms:
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Syndrome
Disease
Pathologic Processes
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents