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

• ClinicalTrials.gov Identifier: NCT04734678
• Recruitment Status: Completed
• First Posted: February 2, 2021
• Last Update Posted: July 20, 2022
• Sponsor: Ain Shams University
• Collaborator: Misr International University
• Information provided by (Responsible Party): Neven Sarhan, Misr International University

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
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: December 1, 2020
• Actual Primary Completion Date: June 1, 2021
• Actual Study Completion Date: August 1, 2021

Groups and Cohorts

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

Outcome Measures

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

Eligibility Criteria

• 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.

Criteria

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.

Contacts and Locations

Locations

Egypt

Teachers Hospital

Cairo, Please Select, Egypt, 11314

Sponsors and Collaborators

Ain Shams University

Misr International University

Investigators

• Principal Investigator: Neven Sarhan, PhD; Misr International University

More Information

• 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
• Last Update Posted: July 20, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

COVID-19; Cytokine Storm; Tocilizumab; Infliximab

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Cytokine Release Syndrome; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Shock; Infliximab; Tumor Necrosis Factor Inhibitors; Anti-Inflammatory Agents; Dermatologic Agents; Gastrointestinal Agents; Antirheumatic Agents