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

Study Overview
=================
Brief 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: 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. 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: 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. 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.

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

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Drug: Tocilizumab
* Drug: Tocilizumab


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Hospitalized, non-critically ill patients with COVID-19 pneumonitis with risk factors for decompensation | Drug: Tocilizumab<br>* 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<br>|
| Experimental: Group B<br>Hospitalized, non-critically ill patients with COVID-19 pneumonitis without risk factors for decompensation | Drug: Tocilizumab<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Response in Maximum Temperature (Tmax) | Number of Participants with Clinical Response in Maximum Temperature (Tmax) | Assessed for the 24 hour period after tocilizumab administration | 
| Number of Participants With Biochemical Response as Determined by CRP Response | 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. | Assessed every 24 hours during patient's hospitalization, up to 4 weeks after tocilizumab administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | 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. | 28 days | 
| Survival to Hospital Discharge | 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. | Hospitalization, up to 4 weeks after tocilizumab administration | 
| Progression of COVID-19 Pneumonitis | 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). | Hospitalization, up to 4 weeks after tocilizumab administration | 
| Rate of Non-elective Mechanical Ventilation | 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. | Hospitalization, up to 4 weeks after tocilizumab administration | 
| Duration of Mechanical Ventilation | This will be a continuous outcome defined by the amount of time between initiation and cessation of mechanical ventilation (invasive and non-invasive). | Hospitalization, up to 4 weeks after tocilizumab administration | 
| Time to Mechanical Ventilation | 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. | Assessed over hospitalization, up to 4 weeks after tocilizumab administration | 
| Rate of Vasopressor/Inotrope Utilization | 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. | Hospitalization, up to 4 weeks after tocilizumab administration | 
| Duration of Vasopressor/Inotrope Utilization | 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). | Hospitalization, up to 4 weeks after tocilizumab administration | 
| Time to Vasopressor or Inotropic Utilization | 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. | Assessed over hospitalization, up to 4 weeks after tocilizumab administration | 
| Number of ICU Days | 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. | Hospitalization, up to 4 weeks after tocilizumab administration | 
| Duration of Increased Supplemental Oxygen Requirement From Baseline | 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. | Assessed over hospitalization, up to 4 weeks after tocilizumab administration |