Tocilizumab in the Treatment of Coronavirus Induced Disease (COVID-19) (CORON-ACT)

CORON-ACT - a Multicenter, Double-blind, Randomized Controlled Phase II Trial on the Efficacy and Safety of Tocilizumab in the Treatment of Coronavirus Induced Disease (COVID-19)

1.) Not possible to recruit the planned number of patients during the planned study period; 2.) "Dexamethason" was included in the standard of care for the study population during the course of the study and inclusion criteria could no longer be met.

The mortality rate of the disease caused by the corona virus induced disease (COVID-19) has been estimated to be 3.7% (WHO), which is more than 10-fold higher than the mortality of influenza. Patients with certain risk factors seem to die by an overwhelming reaction of the immune system to the virus, causing a cytokine storm with features of Cytokine-Release Syndrome (CRS) and Macrophage Activation Syndrome (MAS) and resulting in Acute Respiratory Distress Syndrome (ARDS). Several pro-inflammatory cytokines are elevated in the plasma of patients and features of MAS in COVID-19, include elevated levels of ferritin, d-dimer, and low platelets. There is increasing data that cytokine-targeted biological therapies can improve outcomes in CRS or MAS and even in sepsis. Tocilizumab (TCZ), an anti-IL-6R biological therapy, has been approved for the treatment of CRS and is used in patients with MAS. Based on these data, it is hypothesized that TCZ can reduce mortality in patients with severe COVID-19 prone to CRS and ARDS. The overall purpose of this study is to evaluate whether treatment with TCZ reduces the severity and mortality in patients with COVID-19.

Background and Rationale The Acute Respiratory Syndrome by Corona Virus 2 (SARS-CoV-2), first discovered in December 2019 in Wuhan/China, is causing a worldwide pandemic with potentially lethal implications on an individual basis, and, on the large scale bringing the health care systems and the economy to its limits. The mortality rate of this COronaVIrus induced Disease, COVID-19, has been estimated by the World Health Organization (WHO) to be 3.7%, which is more than 10-fold higher than the mortality of influenza. An infection with SARS-CoV-2 may cause an excessive host immune response, leading to an Acute Respiratory Distress Syndrome (ARDS) and death. Reports from China and from Italy describe an overwhelming inflammation which is triggered by the virus, causing a cytokine storm with features of Cytokine-Release Syndrome (CRS) and/or Macrophage Activation Syndrome (MAS). Pro-inflammatory cytokines such as Interleukin-6 (IL-6) are elevated in the plasma of patients and features of MAS in COVID-19 include elevated levels of ferritin, d-dimer and low platelets. There is increasing evidence, that cytokine-targeted biological therapies can improve outcomes in CRS or MAS and even in sepsis. In recognition of the dramatic development of the COVID-19 pandemic, and in a pragmatic manner, already approved and safe therapies should be evaluated for the use in severe COVID-19. Tocilizumab (TCZ), an anti-IL-6R biological therapy, has been approved for the treatment of CRS and is used in patients with MAS (and in other rheumatologic conditions like Rheumatoid Arthritis (RA) or Giant Cell Arteritis (GCA), with a good safety profile also in the elderly). Collectively, the data strongly suggest that neutralization of the inflammatory pathway induced by IL-6 may reduce mortality in patients with severe COVID-19 prone to CRS and ARDS.

All participants and study personnel involved in patient enrolment, treatment, and follow-up will be masked to group assignment until the final report will be completed and a first interpretation of the results has been done.

Patients get one dose (= 8 mg/kg bodyweight, max. single dose 800 mg) Actemra® (active ingredient: TCZ) intravenously in 100 mL NaCl 0.9% after confirmation of progressive dyspnoea. Infusion time: 60 min. The procedure is repeated once if no improvement in the 8-point WHO scale is observed.

The placebo-controlled intervention is one dose (100 mL) NaCl 0.9% intravenously administered after confirmation of progressive dyspnoea. Infusion time: 60 min. The procedure is repeated once if no improvement in the 8-point WHO scale is observed.

Patients get one dose (= 8 mg/kg bodyweight, max. single dose 800 mg) Actemra® (active ingredient: TCZ) intravenously in 100 mL NaCl 0.9% after confirmation of progressive dyspnoea. Infusion time: 60 min. The procedure is repeated once if no clinical improvement in the 8-point WHO scale is observed.

The placebo-controlled intervention is one dose (100 mL) NaCl 0.9% intravenously administered after confirmation of progressive dyspnoea. Infusion time: 60 min. The procedure is repeated once if no clinical improvement in the 8-point WHO scale is observed.

Events of special interest are defined as secondary infections, acute kidney failure, hepatic, and cardiac failure

Number of patients with SAEs considered by the investigator to be at least probably related to the IMP

Inclusion Criteria: I (first step): Admission to hospital Male or non-pregnant female, ≥60 years of age or ≥30 years of age plus one or more known risk factors (arterial hypertension, diabetes mellitus, coronary heart disease, heart failure, pre-existing chronic pulmonary disease) Confirmed SARS-CoV infection Radiographic evidence compatible with Covid-19 pneumonia (X-ray/CT scan, etc.) Signed Informed Consent Form II (second step; indication for intervention): CRP ≥50mg/L plus 3 out of the following 5 criteria need to be fulfilled: Respiration Rate ≥25 SpO2 <93% (on ambient air) PaO2 <65 mmHg Persistent or increasing dyspnoea as defined by a one point increase on the mMRC dyspnoea scale (over 1 hour) Persistent or increasing oxygen demand (over 1 hour) Exclusion Criteria: I (first step): Patients >80 years of age Patient included in any other interventional trial Indication for imminent or immediate transfer to ICU Treatment with TCZ (or other anti-IL-6R treatment) within 4 weeks prior to baseline Uncontrolled bacterial superinfection according to investigator History of severe allergic reaction to TCZ History of diverticulitis requiring antibiotic treatment or history of colon perforation History of primary immunodeficiency (e.g. CVID) or progressing malignancy History of chronic liver disease (>Child-Pugh A, or according to investigator) II (second step; contraindication for intervention): Alanine transaminase/aspartate transaminase (ALT/AST) >5 times of the upper limit of normal Hemoglobin <80 g/L Leukocytes <2.0 G/L Absolute neutrophil count <1.0 G/L Platelets <50 G/L

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