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

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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

Tracking Information
First Submitted Date  ICMJE April 2, 2020
First Posted Date  ICMJE April 6, 2020
Last Update Posted Date October 14, 2020
Actual Study Start Date  ICMJE April 26, 2020
Actual Primary Completion Date September 27, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 2, 2020)
  • Number of patients with ICU admission [ Time Frame: 7 days after randomisation ]
  • Number of patients with intubation [ Time Frame: 14 days after randomisation ]
  • Number of patients with death [ Time Frame: 28 days after randomisation ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 2, 2020)
  • Illness severity [ Time Frame: At days 2, 7, 14, 28 after randomisation ]
    Assessed by the 8-point WHO scale
  • 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
  • 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
  • Duration of hospitalization (days) [ Time Frame: Up to day 28 after randomisation ]
  • Time to ICU admission (days) [ Time Frame: Up to day 28 after randomisation ]
  • Duration of ICU stay [ Time Frame: Up to day 28 after randomisation ]
  • Time to intubation [ Time Frame: Up to day 28 after randomisation ]
  • Duration of mechanical ventilation (days) [ Time Frame: Up to day 28 after randomisation ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 2, 2020)
  • Number of deaths [ Time Frame: Within 28 days after randomisation ]
  • Number of patients with ICU admission [ Time Frame: Within 28 days after randomisation ]
  • Number of patients with intubation [ Time Frame: Within 28 days after randomisation ]
  • 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
  • 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 ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Tocilizumab in the Treatment of Coronavirus Induced Disease (COVID-19)
Official Title  ICMJE 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)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE SARS-CoV-2 Infection
Intervention  ICMJE
  • 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
  • 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%
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Tocilizumab (TCZ)
  • 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.
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 12, 2020)
5
Original Estimated Enrollment  ICMJE
 (submitted: April 2, 2020)
100
Actual Study Completion Date  ICMJE September 27, 2020
Actual Primary Completion Date September 27, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04335071
Other Study ID Numbers  ICMJE 2020-00691
2020DR2044 ( Other Identifier: Swissmedic )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University Hospital Inselspital, Berne
Study Sponsor  ICMJE University Hospital Inselspital, Berne
Collaborators  ICMJE Roche Pharma AG
Investigators  ICMJE
Study Chair: Peter M. Villiger, Prof. Dr. med. University Hospital Bern (Inselspital)
PRS Account University Hospital Inselspital, Berne
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP