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Comparison of Tocilizumab Versus Tocilizumab/Infliximab in Patients With COVID-19-associated Cytokine Storm Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT04734678
Recruitment Status : Completed
First Posted : February 2, 2021
Last Update Posted : July 20, 2022
Misr International University
Information provided by (Responsible Party):
Neven Sarhan, Misr International University

Brief Summary:

Since the end of 2019, Egypt and the whole world have been suffering from the Coronavirus Disease 2019 (COVID-19) pandemic, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to the World Health Organization (WHO), since the emergence of this new pandemic, there have been more than 97 million confirmed cases of COVID-19 patients and two million death globally; around 160 thousand of these cases are in Egypt.

Tocilizumab play role among the unique therapeutic alternatives for the management of cytokine release syndrome (CRS), a life-threatening complication of chimeric antigen receptor (CAR) - T cell therapy. CRS occurs as a result of uncontrolled immune activation with release of pro-inflammatory cytokines and chemokines. Up till now, clinical trial and expertise with tocilizumab in COVID-19 patients has been limited. Despite preliminary encouraging results, recent studies suffered from limitations such as the absence of consistent treatment outline, a short post-treatment follow-up, and the absence of a comparison group.

A recent study discussed the possible beneficial effect of tumor necrosis factor (TNF) inhibitors in severe COVID-19. Specifically, TNF may aggravate lymphopenia through direct killing via TNF/TNFR1 signaling in T cells, and T cell dysfunction reveals an important yet underestimated target for immunomodulatory therapeutic approaches. Accordingly, anti-TNF may be considered as an encouraging therapeutic option in severe COVID-19.

These promising clinical findings encouraged us to use infliximab (IFX), a chimeric monoclonal anti-TNF antibody, as an experimental therapy in patients with moderate and severe COVID-19 in the absence of IBD.

In this study, we compare the outcomes of a large cohort of patients with moderate and severe COVID-19 pneumonia treated with tocilizumab in addition to standard management, with those of concomitantly hospitalized patients who received infliximab and tocilizumab in addition to standard management.

Condition or disease Intervention/treatment
Covid19 Cytokine Storm Corona Virus Infection Drug: Tocilizumab Drug: Infliximab

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Study Type : Observational
Actual Enrollment : 153 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: Comparison of Tocilizumab Versus Tocilizumab/Infliximab in Patients With COVID-19-associated Cytokine Storm Syndrome
Actual Study Start Date : December 1, 2020
Actual Primary Completion Date : June 1, 2021
Actual Study Completion Date : August 1, 2021

Resource links provided by the National Library of Medicine

Group/Cohort Intervention/treatment
Group 1
Moderate and severe patients who were infected with SARS-CoV-2 and received treatment with tocilizumab in addition to standard management.
Drug: Tocilizumab
400 mg IV only once
Other Name: Actemra

Group 2
Moderate and severe patients who were infected with SARS-CoV-2 and received treatment with infliximab and tocilizumab in addition to standard management.
Drug: Tocilizumab
400 mg IV only once
Other Name: Actemra

Drug: Infliximab
5 mg/kg/day IV for 2 doses 12-24 hours
Other Name: Remicade

Primary Outcome Measures :
  1. Patients' clinical status improvement using six category scale [ Time Frame: Two weeks ]
    The categories were defined as follows: 1) patient discharged, 2) hospitalization not requiring supplemental oxygen, 3) hospitalization requiring supplemental low-flow oxygen, 4) hospitalization requiring high-flow supplemental oxygen, 5) hospitalization requiring invasive mechanical ventilation, 6) death.

  2. Time to improvement in oxygenation [ Time Frame: 48 hours ]
    Increase in SpO2/FiO2 of 50 or greater compared to the baseline SpO2/FiO2

  3. Duration of hospitalization [ Time Frame: Two weeks ]
    Total admission period

  4. Mortality rate [ Time Frame: Two weeks ]
    Death during hospitalization

Secondary Outcome Measures :
  1. Incidence of non-invasive mechanical ventilation [ Time Frame: Two weeks ]
    Need for non-invasive mechanical ventilation

  2. Duration of non-invasive mechanical ventilation [ Time Frame: Two weeks ]
    Time required for non-invasive mechanical ventilation

  3. Incidence of invasive mechanical ventilation [ Time Frame: Two weeks ]
    Need for invasive mechanical ventilation

  4. Duration of invasive mechanical ventilation [ Time Frame: Two weeks ]
    Time required for invasive mechanical ventilation

  5. Occurrence of Secondary infections [ Time Frame: Two weeks ]
    Especially Sepsis

  6. Monitoring of adverse events [ Time Frame: Two weeks ]
    Monitoring of adverse events especially elevation of liver enzymes daily

  7. Occurrence of cardiovascular events [ Time Frame: Two weeks ]
    Prevalence of heart failure, tachycardia and hypertension

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Probability Sample
Study Population
All patients received the same background treatment for 5 days, following an Institutional protocol for standard of care: hydroxychloroquine 400 mg daily, lopinavir/ritonavir 400/100 mg twice daily or/and remdisivir 200 mg LD then 100 once daily as a maintenance dose and anti-coagulation prophylaxis with enoxaparin subcutaneously once a day if D-dimmer between 500-1000 or enoxaparin therapeutic subcutaneously twice daily if D-dimmer >1000.

Inclusion Criteria:

  1. Age 18-65 years.
  2. Able to provide informed consent.
  3. Patients hospitalized with pneumonia proved by chest X-ray or CT scan.
  4. Confirmed infection with COVID-2019 using RT-PCR or strongly suspected to be infected with pending confirmation studies.
  5. Hyper-inflammation defined as elevation in either C-reactive protein (CRP, ≥ 100 mg/L, normal values <6 mg/L) or ferritin (≥ 900 ng/mL, normal value <400 ng/mL), in the presence of increased lactate dehydrogenase (LDH, >220 U/L).
  6. And at least one of the following:

    1. Respiratory frequency ≥30/min.
    2. Blood oxygen saturation ≤93% on room air (RA).
    3. Partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) <300 [18].
    4. Worsening of lung involvement, defined as an increase in number and/or extension of pulmonary areas of consolidation, need for increased FiO2 to maintain stable O2 saturation, or worsening O2 saturation of >3% with stable FiO2.

Exclusion Criteria:

  1. Evidence of concomitant bacterial infection.
  2. Concomitant use of other immunosuppressive biologic drugs.
  3. Baseline elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 5-fold the upper limit of the normal range.
  4. Pregnancy.
  5. Treatment with any TNFα inhibitor in the past 30 days.
  6. Known hypersensitivity to any TNFα inhibitor, murine proteins, or any component of the formulation.
  7. Known or suspected active tuberculosis (TB) or a history of incompletely treated or latent TB.
  8. Serious co-morbidity, including:

    1. Myocardial infarction (within last month).
    2. Moderate or severe heart failure (New York Heart Association (NYHA) class III or IV).
    3. Hepatic patients child Pugh class C.

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): NCT04734678

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Teachers Hospital
Cairo, Please Select, Egypt, 11314
Sponsors and Collaborators
Ain Shams University
Misr International University
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Principal Investigator: Neven Sarhan, PhD Misr International University
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Responsible Party: Neven Sarhan, Lecturer at Faculty of Pharmacy, Misr International University
ClinicalTrials.gov Identifier: NCT04734678    
Other Study ID Numbers: COVID-Infliximab
First Posted: February 2, 2021    Key Record Dates
Last Update Posted: July 20, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Neven Sarhan, Misr International University:
Cytokine Storm
Additional relevant MeSH terms:
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Coronavirus Infections
Cytokine Release Syndrome
Pneumonia, Viral
Respiratory Tract Infections
Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Systemic Inflammatory Response Syndrome
Pathologic Processes
Tumor Necrosis Factor Inhibitors
Anti-Inflammatory Agents
Dermatologic Agents
Gastrointestinal Agents
Antirheumatic Agents