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

Sponsor

Ain Shams University (Other)

Overall Status

Completed

CT.gov ID

NCT04734678

Collaborator

Misr International University (Other)

153

Enrollment

Location

Actual Duration (Months)

19.2

Patients Per Site Per Month

Study Details

Study Description

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	Phase
Covid19 Cytokine Storm Corona Virus Infection	Drug: Tocilizumab Drug: Infliximab

Study Design

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 :

Dec 1, 2020

Actual Primary Completion Date :

Jun 1, 2021

Actual Study Completion Date :

Aug 1, 2021

Arms and Interventions

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

Arm

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 Names:

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 Names:

Actemra

Drug: Infliximab

5 mg/kg/day IV for 2 doses 12-24 hours

Other Names:

Remicade

Outcome Measures

Primary Outcome Measures

Patients' clinical status improvement using six category scale [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.
Time to improvement in oxygenation [48 hours]
Increase in SpO2/FiO2 of 50 or greater compared to the baseline SpO2/FiO2
Duration of hospitalization [Two weeks]
Total admission period
Mortality rate [Two weeks]
Death during hospitalization

Secondary Outcome Measures

Incidence of non-invasive mechanical ventilation [Two weeks]
Need for non-invasive mechanical ventilation
Duration of non-invasive mechanical ventilation [Two weeks]
Time required for non-invasive mechanical ventilation
Incidence of invasive mechanical ventilation [Two weeks]
Need for invasive mechanical ventilation
Duration of invasive mechanical ventilation [Two weeks]
Time required for invasive mechanical ventilation
Occurrence of Secondary infections [Two weeks]
Especially Sepsis
Monitoring of adverse events [Two weeks]
Monitoring of adverse events especially elevation of liver enzymes daily
Occurrence of cardiovascular events [Two weeks]
Prevalence of heart failure, tachycardia and hypertension

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Inclusion Criteria:

Age 18-65 years.
Able to provide informed consent.
Patients hospitalized with pneumonia proved by chest X-ray or CT scan.
Confirmed infection with COVID-2019 using RT-PCR or strongly suspected to be infected with pending confirmation studies.
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).
And at least one of the following:
Respiratory frequency ≥30/min.
Blood oxygen saturation ≤93% on room air (RA).
Partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) <300 [18].
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:

Evidence of concomitant bacterial infection.
Concomitant use of other immunosuppressive biologic drugs.
Baseline elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 5-fold the upper limit of the normal range.
Pregnancy.
Treatment with any TNFα inhibitor in the past 30 days.
Known hypersensitivity to any TNFα inhibitor, murine proteins, or any component of the formulation.
Known or suspected active tuberculosis (TB) or a history of incompletely treated or latent TB.
Serious co-morbidity, including:
Myocardial infarction (within last month).
Moderate or severe heart failure (New York Heart Association (NYHA) class III or IV).
Hepatic patients child Pugh class C.