Clinical trial NCT04335071: Tocilizumab in the Treatment of Coronavirus Induced Disease (COVID-19)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: SARS-CoV-2 Infection
Keywords: Covid-19
Pneumonia
Tocilizumab
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2020-04-06
Enrollment: 5
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A multicenter, double-blind, randomized controlled phase II trial
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of patients with ICU admission
timeFrame: 7 days after randomisation
measure: Number of patients with intubation
timeFrame: 14 days after randomisation
measure: Number of patients with death
timeFrame: 28 days after randomisation
Secondary outcomes:
measure: Illness severity
timeFrame: At days 2, 7, 14, 28 after randomisation
measure: Number of patients with clinical improvement
timeFrame: At days 2, 7, 14, 28 after randomisation
measure: Time to clinical improvement (days)
timeFrame: Up to day 28 after randomisation
measure: Duration of hospitalization (days)
timeFrame: Up to day 28 after randomisation
measure: Time to ICU admission (days)
timeFrame: Up to day 28 after randomisation
measure: Duration of ICU stay
timeFrame: Up to day 28 after randomisation
measure: Time to intubation
timeFrame: Up to day 28 after randomisation
measure: Duration of mechanical ventilation (days)
timeFrame: Up to day 28 after randomisation
Other outcomes:
measure: Number of deaths
timeFrame: Within 28 days after randomisation
measure: Number of patients with ICU admission
timeFrame: Within 28 days after randomisation
measure: Number of patients with intubation
timeFrame: Within 28 days after randomisation
measure: Number of patients with events of special interest
timeFrame: Within 28 days after randomisation
measure: Number of patients with SAEs considered by the investigator to be at least probably related to the IMP
timeFrame: Within 28 days after randomisation
Locations:
city: Bern
country: Switzerland
facility: University Hospital Bern (Inselspital)
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
city: Viganello
country: Switzerland
facility: Ospedale Regionale di Lugano (EOC)
city: Zurich
country: Switzerland
facility: University Hospital Zurich
Study officials:
affiliation: University Hospital Bern (Inselspital)
name: Peter M. Villiger, Prof. Dr. med.
role: STUDY_CHAIR
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