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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04335071
Recruitment Status : Terminated (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.)
First Posted : April 6, 2020
Last Update Posted : October 14, 2020
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

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.


Condition or disease Intervention/treatment Phase
SARS-CoV-2 Infection Drug: Tocilizumab (TCZ) Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A multicenter, double-blind, randomized controlled phase II trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
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)
Actual Study Start Date : April 26, 2020
Actual Primary Completion Date : September 27, 2020
Actual Study Completion Date : September 27, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Tocilizumab

Arm Intervention/treatment
Experimental: Actemra
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.
Drug: Tocilizumab (TCZ)
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.
Other Name: Actemra

Placebo Comparator: Placebo
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.
Drug: Placebo
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.
Other Name: NaCl 0.9%




Primary Outcome Measures :
  1. Number of patients with ICU admission [ Time Frame: 7 days after randomisation ]
  2. Number of patients with intubation [ Time Frame: 14 days after randomisation ]
  3. Number of patients with death [ Time Frame: 28 days after randomisation ]

Secondary Outcome Measures :
  1. Illness severity [ Time Frame: At days 2, 7, 14, 28 after randomisation ]
    Assessed by the 8-point WHO scale

  2. Number of patients with clinical improvement [ Time Frame: At days 2, 7, 14, 28 after randomisation ]
    Clinical improvement is defined as a ≥ 2-point improvement in the 8-point WHO scale

  3. Time to clinical improvement (days) [ Time Frame: Up to day 28 after randomisation ]
    Clinical improvement is defined as a ≥ 2-point improvement in the 8-point WHO scale

  4. Duration of hospitalization (days) [ Time Frame: Up to day 28 after randomisation ]
  5. Time to ICU admission (days) [ Time Frame: Up to day 28 after randomisation ]
  6. Duration of ICU stay [ Time Frame: Up to day 28 after randomisation ]
  7. Time to intubation [ Time Frame: Up to day 28 after randomisation ]
  8. Duration of mechanical ventilation (days) [ Time Frame: Up to day 28 after randomisation ]

Other Outcome Measures:
  1. Number of deaths [ Time Frame: Within 28 days after randomisation ]
  2. Number of patients with ICU admission [ Time Frame: Within 28 days after randomisation ]
  3. Number of patients with intubation [ Time Frame: Within 28 days after randomisation ]
  4. Number of patients with events of special interest [ Time Frame: Within 28 days after randomisation ]
    Events of special interest are defined as secondary infections, acute kidney failure, hepatic, and cardiac failure

  5. Number of patients with SAEs considered by the investigator to be at least probably related to the IMP [ Time Frame: Within 28 days after randomisation ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   30 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04335071


Locations
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Switzerland
University Hospital Bern (Inselspital)
Bern, Switzerland, 3010
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, Switzerland, 1011
Ospedale Regionale di Lugano (EOC)
Viganello, Switzerland, 6962
University Hospital Zurich
Zurich, Switzerland, 8091
Sponsors and Collaborators
University Hospital Inselspital, Berne
Roche Pharma AG
Investigators
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Study Chair: Peter M. Villiger, Prof. Dr. med. University Hospital Bern (Inselspital)
Publications:

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Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT04335071    
Other Study ID Numbers: 2020-00691
2020DR2044 ( Other Identifier: Swissmedic )
First Posted: April 6, 2020    Key Record Dates
Last Update Posted: October 14, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital Inselspital, Berne:
Covid-19
Pneumonia
Tocilizumab
Additional relevant MeSH terms:
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Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases