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

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.

Study Overview

• Status: Completed
• Conditions: Covid19; Corona Virus Infection; Cytokine Storm
• Intervention / Treatment: Drug: Tocilizumab; Drug: Infliximab

• Study Type: Observational
• Enrollment (Actual): 153

Contacts and Locations

Study Locations

• Egypt
  • Please Select
    • Cairo, Please Select, Egypt, 11314
      • Teachers Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders 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.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

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 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Ain Shams University
• Collaborators: Misr International University

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Actual): June 1, 2021
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: January 31, 2021
• First Submitted That Met QC Criteria: February 1, 2021
• First Posted (Actual): February 2, 2021

Study Record Updates

• Last Update Posted (Actual): July 20, 2022
• Last Update Submitted That Met QC Criteria: July 19, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; Tocilizumab; Infliximab; Cytokine Storm
• Additional Relevant MeSH Terms: Pathologic Processes; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock; COVID-19; Coronavirus Infections; Cytokine Release Syndrome; Antirheumatic Agents; Gastrointestinal Agents; Dermatologic Agents; Infliximab
• Other Study ID Numbers: COVID-Infliximab

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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