Clinical trial NCT04734678: Comparison of Tocilizumab Versus Tocilizumab/Infliximab in Patients With COVID-19-associated Cytokine Storm Syndrome
Official title: Comparison of Tocilizumab Versus Tocilizumab/Infliximab in Patients With COVID-19-associated Cytokine Storm Syndrome
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Covid19
Cytokine Storm
Corona Virus Infection
Keywords: COVID-19
Cytokine Storm
Tocilizumab
Infliximab
Lead sponsor: Ain Shams University
Sponsor class: OTHER
Collaborators: name: Misr International University
First posted: 2021-02-02
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: OTHER
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.

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.


Eligibility 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.

Primary outcomes:
measure: Patients' clinical status improvement using six category scale
timeFrame: Two weeks
measure: Time to improvement in oxygenation
timeFrame: 48 hours
measure: Duration of hospitalization
timeFrame: Two weeks
measure: Mortality rate
timeFrame: Two weeks
Secondary outcomes:
measure: Incidence of non-invasive mechanical ventilation
timeFrame: Two weeks
measure: Duration of non-invasive mechanical ventilation
timeFrame: Two weeks
measure: Incidence of invasive mechanical ventilation
timeFrame: Two weeks
measure: Duration of invasive mechanical ventilation
timeFrame: Two weeks
measure: Occurrence of Secondary infections
timeFrame: Two weeks
measure: Monitoring of adverse events
timeFrame: Two weeks
measure: Occurrence of cardiovascular events
timeFrame: Two weeks
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: Teachers Hospital
state: Please Select
Study officials:
affiliation: Misr International University
name: Neven Sarhan, PhD
role: PRINCIPAL_INVESTIGATOR
References: