Clinical trial NCT04332913: Efficacy and Safety of Tocilizumab in the Treatment of SARS-Cov-2 Related Pneumonia
Official title: Efficacy and Safety of Tocilizumab in the Treatment of Patients With Respiratory Distress Syndrome and Cytokine Release Syndrome Secondary to COVID-19: a Proof of Concept Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: COVID-19 Pneumonia
Keywords: Tocilizumab
Lead sponsor: University of L'Aquila
Sponsor class: OTHER
First posted: 2020-04-03
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: COVID-19 patients with pneumonia requiring hospitalization

Brief summary: The current spread of the COrona VIrus Disease-2019 (COVID-19) epidemic in Italy, and the current lack of effective and approved drugs for its treatment, poses the problem of Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected patients management, especially those who underwent to experience COVID-19 complications, such as CRS. This unmet need becomes more severe if the investigator consider that, the COVID-19 mortality stands around 2% in the general population, but it rises to 49% when considering intensive care unit (ICU) patients. To increase the chances of survival of these patients, the compassionate use of the available drugs is required, based on literature data, to the best of our abilities. ICU patients with cytokine release syndrome (CRS) secondary to COVID-19, show increased production of pro-inflammatory cytokines, including interleukin (IL-6), IL-2, IL-7, IL-10, tumor necrosis factor (TNF)-α and interferon (INF)γ, similar to that found in patients who develop CRS secondary to Chimeric Antigen Receptor-T (CAR-T) therapy. Although immuno-modulatory therapy is not routinely recommended in COVID-19 pneumonia, tocilizumab might have a rationale in those patients who develop CRS, blocking the complications caused by high levels of IL-6, and possibly preventing the development of a multi-organ failure. Reassuring data in this sense, come from the first studies conducted in China. In a Chinese pilot study, Xiaoling Xu and collaborators used tocilizumab (at a dosage of 400 mg iv in a single dose, with a possible second dose in case of no clinical response) in patients with COVID-19 in the presence of one of the following criteria: i) respiratory rate ≥ 30 acts/min; ii) SpO2 ≤ 93% in ambient air; iii) PaO2/FiO2 ≤ 300 mmHg. In the 21 patients treated with tocilizumab a significant reduction in IL-6 levels and fever, with improvement in lung function, was demonstrated. Besides, 90% of treated patients showed an improvement in the radiological picture, in terms of a decrease in the frosted glass areas, and a return to normal lymphocytes count in the peripheral blood. This is a prospective observational clinical study and it is aimed at verifying tocilizumab efficacy and safety in patients with COVID-19 complicated by acute distress respiratory syndrome (ARDS) and CRS.


Eligibility criteria: Inclusion Criteria:

* All gender patients aged ≥ 18 years;
* Patients with SARS-CoV-2 infection confirmed by tests (RT-PCR) and pulmonary involvement, hospitalized, at the end of the initial phase of high viral load of COVID-19 (apyretic\> 72 hours and / or at least 7 days after onset of symptoms);
* Worsening of respiratory exchanges such as to require non-invasive or invasive ventilation support (BCRSS score ≥ 3).
* High levels of IL-6 (\> 40 pg/mL) or alternatively CRP and/or ferritin and/or D-dimer and/or fibrinogen values higher than the reference values or rapidly increasing;
* Signature of informed consent.

Exclusion Criteria:

* Alanine aminotransferase and/or Aspartate aminotransferase (ALT / AST) \> 5 times compared to normal laboratory values.
* Presence of a chronic renal failure ≥ 4 stage (glomerular filtrate values \<30 ml/min/1.73 m2).
* Presence of neutropenia (neutrophils count \< 500 / mm3).
* Platelet count less than 50 x 103/μL.
* Documented sepsis from other pathogens other than SARS-CoV-2.
* Presence of co-morbidities associated, in clinical judgment, with an unfavourable outcome.
* Complicated diverticulitis and / or intestinal perforation.
* Skin infection in progress (e.g. dermohypodermitis not controlled by antibiotic therapy).
* Immuno-suppressive anti-rejection therapy.
* Pregnancy or woman of childbearing age who does not use contraceptive and/or breastfeeding measures.
* Previous ischemic attack or myocardial infarction.
* NYHA class III or IV heart failure.
* Severe depressive syndrome or other psychiatric disease which, in the opinion of the doctor, can preclude patient participation in the study.
* Presence of known malignant neoplasms.
* Clinically significant history of alcohol abuse or drug addiction which, in the opinion of the doctor, may preclude the subject's participation in the study.
* Any condition which, in the opinion of the doctor, precludes the possibility of using the study drug provided for in the RCP.
* Any other laboratory condition or parameter that, in the doctor's judgment, precludes the subject's participation in the study.

Primary outcomes:
measure: Percentage of patients with complete recovery defined as fever disappearance and return to normal peripheral oxygen saturation values (SpO2) after 14 days from the end of treatment with tocilizumab.
timeFrame: 14 days
Secondary outcomes:
measure: Percentage of patients achieving a score <3 on the Brescia-COVID respiratory severity scale (BCRSS) after the last tocilizumab administration.
timeFrame: 24 hours
measure: Percentage of patients with partial recovery defined as the disappearance of fever 14 days after the end of treatment with tocilizumab.
timeFrame: 14 days
measure: Duration of hospitalization
timeFrame: 14 days
measure: Time to the first negative SARS-CoV-2 negative RT-PCR test
timeFrame: 14 days
measure: Changes from the baseline in the white blood cell count
timeFrame: 7, 14 days
measure: Changes from the baseline in the lymphocyte populations (cluster of differentiation (CD)3+CD4+, CD3+CD8+, CD19+, Th17)
timeFrame: 7, 14 days
measure: Changes from the baseline of c-reactive protein (CRP) values
timeFrame: 7, 14 days
measure: Changes from the baseline of Ferritin values
timeFrame: 7, 14 days
measure: Changes from the baseline of BNP values
timeFrame: 7,14 days
measure: Changes from the baseline of CK-MB values
timeFrame: 7,14 days
measure: Changes from the baseline of Troponin values
timeFrame: 7,14 days
measure: Changes from the baseline of LDH values
timeFrame: 7,14 days
measure: Changes from the baseline of myoglobulin values
timeFrame: 7,14 days
measure: Changes in myocardial ischemia signs at the electrocardiographic trace (YES or NO)
timeFrame: 7,14 days
measure: Rate of adverse events report during and after tocilizumab
timeFrame: 14 days
measure: Mortality (number of Partecipants, cause and timing)
timeFrame: 12 weeks
measure: Percentage of patients who develop autoimmune diseases
timeFrame: 1 year
Other outcomes:
Locations:
city: L'Aquila
country: Italy
facility: Ospedale San Salvatore
Study officials:
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