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Completed

NCT Number: NCT04331795

Tocilizumab to Prevent Clinical Decompensation in Hospitalized, Non-critically Ill Patients With COVID-19 Pneumonitis

Coronavirus disease-2019 (COVID-19) has a quoted inpatient mortality as high as 25%. This high mortality may be driven by hyperinflammation resembling cytokine release syndrome (CRS), offering the hope that therapies targeting the interleukin-6 (IL-6) axis therapies commonly used to treat CRS can be used to reduce COVID-19 mortality. Retrospective analysis of severe to critical COVID-19 patients receiving tocilizumab demonstrated that the majority of patients had rapid resolution (i.e., within 24-72 hours following administration) of both clinical and biochemical signs (fever and CRP, respectively) of hyperinflammation with only a single tocilizumab dose.

Hypotheses:

1. Tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients with clinical risk factors for clinical decompensation, intensive care utilization, and death. 2. Low-dose tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients with and without clinical risk factors for clinical decompensation, intensive care utilization, and death.

Objectives:

1. To establish proof of concept that tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients with clinical risk factors for clinical decompensation, intensive care utilization, and death, as determined by the clinical outcome of resolution of fever and the biochemical outcome measures of time to CRP normalization for the individual patient and the rate of patients whose CRP normalize. 2. To establish proof of concept that low-dose tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients without clinical risk factors for clinical decompensation, intensive care utilization, and death, as determined by the clinical outcome of resolution of fever and the biochemical outcome measures of time to CRP normalization for the individual patient and the rate of patients whose CRP normalize.

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Key information

Conditions

COVID-19 Coronaviridae Infections Coronavirus Infections Infections Lung Diseases Nidovirales Infections Pneumonia Pneumonia, Viral RNA Virus Infections Respiratory Tract Diseases Respiratory Tract Infections Virus Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

University of Chicago Medicine

Chicago, Illinois, 60637, United States

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Adults ≥ 18 years of age
  • Approval from the patient's primary service
  • Admitted as an inpatient to University of Chicago Medicine
  • Fever, documented in electronic medical record and defined as: T ≥ 38*C by any conventional clinical method (forehead, tympanic, oral, axillary, rectal)
  • Positive test for active SARS-CoV-2 infection
  • Radiographic evidence of infiltrates on chest radiograph (CXR) or computed tomography (CT)
  • Ability to provide written informed consent on the part of the subject or, in the absence of decisional capacity of the subject, an appropriate surrogate (e.g. a legally authorized representative).

Exclusion criteria

  • Concurrent use of invasive mechanical ventilation (patients receiving non-invasive mechanical ventilation [CPAP, BiPap, HHFNC] are eligible)
  • Concurrent use of vasopressor or inotropic medications
  • Previous receipt of tocilizumab or another anti-IL6R or IL-6 inhibitor.
  • Known history of hypersensitivity to tocilizumab.
  • Patients who are actively being considered for a study of an antiviral agent that would potentially exclude concurrent enrollment on this study.
  • Patients actively receiving an investigational antiviral agent in the context of a clinical research study.
  • Diagnosis of end-stage liver disease or listed for liver transplant.
  • Elevation of AST or ALT in excess of 5 times the upper limit of normal.
  • Neutropenia (Absolute neutrophil count < 500/uL).
  • Thrombocytopenia (Platelets < 50,000/uL).
  • On active therapy with a biologic immunosuppressive agent, which include the following biologics and any biosimilar versions thereof:
  • Alemtuzumab
  • Blinatumomab
  • Brentuximab
  • Daratumumab
  • Elotuzumab
  • Ibritumomab
  • Obinutuzumab
  • Ofatumumab
  • Ocrelizumab
  • Rituximab
  • Inotuzumab
  • Gemtuzumab
  • Tositumumab
  • Moxetumomab
  • Polatuzumab
  • Abatacept
  • Adalimumab
  • Belimumab
  • Certolizumab
  • Eculizumab
  • Etanercept
  • Golimumab
  • Infliximab
  • Ixekizumab
  • Rituximab
  • Sarilumab
  • Secukinumab
  • Tocilizumab
  • Ustekinumab
  • On active therapy with a JAK2-targeted agent, which include the following:
  • Tofacitinib
  • Baricitinib
  • Upadacitinib
  • Ruxolitinib
  • History of bone marrow transplantation or solid organ transplant.
  • Known history of Hepatitis B or Hepatitis C.
  • Known history of mycobacterium tuberculosis infection at risk for reactivation.
  • Known history of gastrointestinal perforation or active diverticulitis.
  • Multi-organ failure as determined by primary treating team
  • Any other documented serious, active infection besides COVID-19.
  • Pregnant patients
  • Patients who are unable to discontinue scheduled antipyretic medications, either as monotherapy (e.g., acetaminophen or ibuprofen [aspirin is acceptable]) or as part of combination therapy (e.g., hydrocodone/acetaminophen, aspirin/acetaminophen/caffeine [Excedrin®])
  • CRP < 40 mg/L (or ug/mL)

Patients will be assigned to Group A if:

● C-reactive protein (CRP) ≥ 75 ug/mL

AND

Any one of the following criteria are met:

  • Previous ICU admission
  • Previous non-elective intubation
  • Admission for heart failure exacerbation within the past 12 months
  • History of percutaneous coronary intervention (PCI)
  • History of coronary artery bypass graft (CABG) surgery
  • Diagnosis of pulmonary hypertension
  • Baseline requirement for supplemental O2
  • Diagnosis of interstitial lung disease (ILD)
  • Admission for chronic obstructive pulmonary disease (COPD) exacerbation within the past 12 months
  • Asthma with use of daily inhaled corticosteroid
  • History of pneumonectomy or lobectomy
  • History of radiation therapy to the lung
  • History of HIV
  • Cancer of any stage and receiving active treatment (excluding hormonal therapy)
  • Any history of diagnosed immunodeficiency
  • End-stage renal disease (ESRD) requiring peritoneal or hemodialysis
  • History of cerebrovascular accident with residual, patient-reported neurologic deficit
  • BMI >30 kg/m2
  • Supplemental O2 requirement > 6L in the 24 hours prior to enrollment and tocilizumab administration

All other eligible patients assigned to Group B

Treatment and study plan

Tocilizumab

Drug

Group A: Tocilizumab (beginning dose 200mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours.

Second dose is provisioned if:

  • Increasing supplemental oxygen requirement or Tmax higher than baseline in the 24h following initial tocilizumab administration AND
  • CRP decrease is < 25% at 24 hours following tocilizumab administration and CRP > 40mg/L

Primary outcomes

  1. Number of Participants With Clinical Response in Maximum Temperature (Tmax)

    Time frame: Assessed for the 24 hour period after tocilizumab administration

    Number of Participants with Clinical Response in Maximum Temperature (Tmax)

  2. Number of Participants With Biochemical Response as Determined by CRP Response

    Time frame: Assessed every 24 hours during patient's hospitalization, up to 4 weeks after tocilizumab administration

    Number of Participants with Biochemical Response as determined by CRP Response. Defined as at least 25% decrease in CRP from baseline at least 16 hours after administration of drug.

Secondary outcomes

  1. Overall Survival

    Time frame: 28 days

    28-Day Overall Survival is defined as the status of the patient at the end of 28 days, beginning from the time of the first dose of tocilizumab.

  2. Survival to Hospital Discharge

    Time frame: Hospitalization, up to 4 weeks after tocilizumab administration

    This will be defined as the percentage of patients who are discharged in stable condition compared to the percentage of patients who die in the hospital. Patients who are discharged to hospice will be excluded from this calculation.

  3. Progression of COVID-19 Pneumonitis

    Time frame: Hospitalization, up to 4 weeks after tocilizumab administration

    This will be a binary outcome defined by worsening COVID-19 pneumonitis resulting in transition from clinical Group A or Group B COVID-19 pneumonitis to critical COVID-19 pneumonitis during the course of the patient's COVID-19 infection. This diagnosis will be determined by treating physicians on the basis of worsening pulmonary infiltrates on chest imaging as well as clinical deterioration marked by persistent fever, rising supplemental oxygen requirement, declining PaO2/FiO2 ratio, and the need for intensive care such as mechanical ventilation or vasopressor/inotrope medication(s).

  4. Rate of Non-elective Mechanical Ventilation

    Time frame: Hospitalization, up to 4 weeks after tocilizumab administration

    This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of non-invasive (BiPap, heated high-flow nasal cannula) or invasive positive pressure ventilation during the course of the patient's COVID-19 infection. For patients admitted to the hospital using non-invasive mechanical ventilation, the utilization of mechanical ventilation will count toward this metric, as well. Calculated as the ratio of the number of patients who require non-invasive or invasive positive pressure ventilation during hospitalization and total number of patients who receive tocilizumab.

  5. Duration of Mechanical Ventilation

    Time frame: Hospitalization, up to 4 weeks after tocilizumab administration

    This will be a continuous outcome defined by the amount of time between initiation and cessation of mechanical ventilation (invasive and non-invasive).

  6. Time to Mechanical Ventilation

    Time frame: Assessed over hospitalization, up to 4 weeks after tocilizumab administration

    This will be a continuous outcome defined by the amount of time between tocilizumab dose administration and the initiation of mechanical ventilation. This will be treated as a time-to-event with possible censoring.

  7. Rate of Vasopressor/Inotrope Utilization

    Time frame: Hospitalization, up to 4 weeks after tocilizumab administration

    This will be a binary outcome defined as utilization of any vasopressor or inotropic medication during the course of the patient's COVID-19 infection. Calculated as the ratio of the number of patients who require vasopressor or inotrope medication during hospitalization and total number of patients who receive tocilizumab.

  8. Duration of Vasopressor/Inotrope Utilization

    Time frame: Hospitalization, up to 4 weeks after tocilizumab administration

    This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor or inotrope medication(s).

  9. Time to Vasopressor or Inotropic Utilization

    Time frame: Assessed over hospitalization, up to 4 weeks after tocilizumab administration

    This will be a continuous outcome defined by the amount of time between first tocilizumab dose administration and the initiation of vasopressor or inotropic medication(s). This will be treated as a time-to-event with possible censoring.

  10. Number of ICU Days

    Time frame: Hospitalization, up to 4 weeks after tocilizumab administration

    Number of ICU days is defined as the time period when a patient is admitted to the ICU (defined as the timestamp on the first vital signs collected in an ICU) until they are transferred from the ICU to a non-ICU setting such as a general acute care bed (defined as the timestamp on the first vital signs collected outside an ICU, excepting any "off the floor" vital signs charted from operating rooms or procedure or imaging suites). Death in the ICU will be a competing risk.

  11. Duration of Increased Supplemental Oxygen Requirement From Baseline

    Time frame: Assessed over hospitalization, up to 4 weeks after tocilizumab administration

    Duration of increased supplemental oxygen requirement from baseline is defined as the time period (number of days) during which the participant requires supplemental oxygen in excess of his/her baseline supplemental oxygen requirement. The supplemental oxygen requirement is defined as the highest liters-per-minute flow of supplemental oxygen required by the patient each day over the course of the hospitalization.

Sponsors and collaborators

Lead sponsor

University of Chicago

Other

Registry information

Official study title

Early Institution of Tocilizumab Titration in Non-Critical Hospitalized COVID-19 Pneumonitis

Acronym: COVIDOSE

Important dates

Study start
2020
Primary completion
2020
Study completion
2020
First posted
Apr 2, 2020
Registry last updated
Jun 9, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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