Tocilizumab to Prevent Clinical Decompensation in Hospitalized, Non-critically Ill Patients With COVID-19 Pneumonitis
Condition: COVID-19
MeSH terms: COVID-19; Pneumonia
Intervention: Tocilizumab; Tocilizumab
Intervention description: 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; Group B: Low-dose tocilizumab (beginning dose 80mg) 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
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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