Clinical trial NCT04331795: Tocilizumab to Prevent Clinical Decompensation in Hospitalized, Non-critically Ill Patients With COVID-19 Pneumonitis
Official title: Early Institution of Tocilizumab Titration in Non-Critical Hospitalized COVID-19 Pneumonitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Lead sponsor: University of Chicago
Sponsor class: OTHER
First posted: 2020-04-02
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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:

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

Primary outcomes:
measure: Number of Participants With Clinical Response in Maximum Temperature (Tmax)
timeFrame: Assessed for the 24 hour period after tocilizumab administration
measure: Number of Participants With Biochemical Response as Determined by CRP Response
timeFrame: Assessed every 24 hours during patient's hospitalization, up to 4 weeks after tocilizumab administration
Secondary outcomes:
measure: Overall Survival
timeFrame: 28 days
measure: Survival to Hospital Discharge
timeFrame: Hospitalization, up to 4 weeks after tocilizumab administration
measure: Progression of COVID-19 Pneumonitis
timeFrame: Hospitalization, up to 4 weeks after tocilizumab administration
measure: Rate of Non-elective Mechanical Ventilation
timeFrame: Hospitalization, up to 4 weeks after tocilizumab administration
measure: Duration of Mechanical Ventilation
timeFrame: Hospitalization, up to 4 weeks after tocilizumab administration
measure: Time to Mechanical Ventilation
timeFrame: Assessed over hospitalization, up to 4 weeks after tocilizumab administration
measure: Rate of Vasopressor/Inotrope Utilization
timeFrame: Hospitalization, up to 4 weeks after tocilizumab administration
measure: Duration of Vasopressor/Inotrope Utilization
timeFrame: Hospitalization, up to 4 weeks after tocilizumab administration
measure: Time to Vasopressor or Inotropic Utilization
timeFrame: Assessed over hospitalization, up to 4 weeks after tocilizumab administration
measure: Number of ICU Days
timeFrame: Hospitalization, up to 4 weeks after tocilizumab administration
measure: Duration of Increased Supplemental Oxygen Requirement From Baseline
timeFrame: Assessed over hospitalization, up to 4 weeks after tocilizumab administration
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
Study officials:
affiliation: University of Chicago, Department of Medicine, Section of Rheumatology
name: Pankti Reid, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Strohbehn GW, Heiss BL, Rouhani SJ, Trujillo JA, Yu J, Kacew AJ, Higgs EF, Bloodworth JC, Cabanov A, Wright RC, Koziol AK, Weiss A, Danahey K, Karrison TG, Edens CC, Bauer Ventura I, Pettit NN, Patel BK, Pisano J, Strek ME, Gajewski TF, Ratain MJ, Reid PD. COVIDOSE: A Phase II Clinical Trial of Low-Dose Tocilizumab in the Treatment of Noncritical COVID-19 Pneumonia. Clin Pharmacol Ther. 2021 Mar;109(3):688-696. doi: 10.1002/cpt.2117. Epub 2020 Dec 10.