Low-dose Tocilizumab Versus Standard of Care in Hospitalized Patients With COVID-19 (COVIDOSE-2)

  • STATUS
    Recruiting
  • End date
    Mar 1, 2025
  • participants needed
    332
  • sponsor
    University of Chicago
Updated on 26 May 2022
interleukin-6
pneumonia
fever
chest radiograph
covid-19
SARS
tocilizumab

Summary

Tocilizumab is an effective treatment for severe coronavirus disease 2019 (Covid-19) pneumonia and related inflammation. Given limited global supplies, clarification of the optimal tocilizumab dose is critical. We conducted an open-label, randomized, controlled trial evaluating two different dose levels of tocilizumab in Covid-19 (40mg and 120mg). Randomization was stratified on remdesivir and corticosteroid at enrollment. The primary outcome was the time to recovery. The key secondary outcome was 28-day mortality.

Description

COVID-19's high mortality may be driven by hyperinflammation. Interleukin-6 (IL-6) axis therapies may reduce COVID-19 mortality. Retrospective analyses of tocilizumab in severe to critical COVID-19 patients have demonstrated survival advantage and lower likelihood of requiring invasive ventilation following tocilizumab administration. The majority of patients have 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.

The investigators hypothesized that a dose of tocilizumab significantly lower than the EMAand FDA-labeled dose (8mg/kg) as well as the emerging standard of care dose (400mg) may be effective in patients with COVID-19 pneumonitis and hyperinflammation. Advantages to the lower dose of tocilizumab may include lower likelihood of secondary bacterial infections as well as extension of this drug's limited supply. The investigators conducted an adaptive single-arm phase 2 trial (NCT04331795) evaluating clinical and biochemical response to low-dose tocilizumab in patients with COVID-19 pneumonitis and hyperinflammation.

This multi-center, prospective, randomized controlled phase 2 trial -- designed as two sub-studies to allow for the possible emergence of data demonstrating the clinical efficacy of tocilizumab 8mg/kg or 400mg -- formally tests the clinical efficacy of low-dose tocilizumab in COVID-19 pneumonia.

Sub-Study A Primary Objective A: To establish whether low-dose tocilizumab reduces the time to clinical recovery in patients with COVID-19 pneumonitis and hyperinflammation, when compared to a tocilizumab-free standard of care.

Hypothesis A: The investigators hypothesize that low-dose tocilizumab, when compared to a tocilizumab-free standard of care, decreases the time to recovery in hospitalized, non-invasively ventilated patients with COVID-19 pneumonitis and hyperinflammation by three days or more.

Sub-Study B Primary Objective B: To establish whether low-dose tocilizumab is near-equivalent to high-dose tocilizumab (400mg or 8 mg/kg) in reducing the time to clinical recovery in patients with COVID-19 pneumonitis and hyperinflammation.

Hypothesis B: The investigators hypothesize that low-dose tocilizumab is near-equivalent to high-dose tocilizumab in reducing the time to clinical recovery in hospitalized, non-invasively ventilated patients with COVID-19 pneumonitis and hyperinflammation.

Details
Condition COVID-19
Treatment Tocilizumab, Standard of Care
Clinical Study IdentifierNCT04479358
SponsorUniversity of Chicago
Last Modified on26 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Adults ≥ 18 years of age
Approval from the patient's primary inpatient service
Hospitalized
Fever, documented in electronic medical record and defined as: T ≥ 38 degrees 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
Concurrent use of vasopressor or inotropic medications
Previous receipt of tocilizumab or another anti-IL6R or IL-6 inhibitor in the year prior
Known history of hypersensitivity to tocilizumab
Diagnosis of end-stage liver disease or listed for liver transplant
Elevation of AST or ALT in excess of 10 times the upper limit of normal
Neutropenia (Absolute neutrophil count < 500/uL)
Thrombocytopenia (Platelets < 50,000/uL)
On active therapy with a Bruton's tyrosine kinase-targeted agent, which include the
following
Acalabrutinib
Ibrutinib
Zanubrutinib
On active therapy with a JAK2-targeted agent, which include the following
Tofacitinib
Baricitinib
Upadacitinib
Ruxolitinib
Any of the following biologic immunosuppressive agent (and any biosimilar versions thereof) administered in the past 6 months or less
Abatacept
Adalimumab
Alemtuzumab
Atezolizumab
Belimumab
Blinatumomab
Brentuximab
Certolizumab
Daratumumab
Durvalumab
Eculizumab
Elotuzumab
Etanercept
Gemtuzumab
Golimumab
Ibritumomab
Infliximab
Inotuzumab
Ipilimumab
Ixekizumab
Moxetumomab
Nivolumab
Obinutuzumab
Ocrelizumab
Ofatumumab
Pembrolizumab
Polatuzumab
Rituximab
Rituximab
Sarilumab
Secukinumab
Tocilizumab
Tositumumab
Tremelimumab
Urelumab
Ustekinumab
History of bone marrow transplantation (including chimeric antigen receptor T-cell) or solid organ transplant
Known history of Hepatitis B or Hepatitis C (patients who have completed curative-intent anti-HCV treatments are not excluded from trial)
Positive result on hepatitis B or C screening
Known history of mycobacterium tuberculosis infection at risk for reactivation
Known history of gastrointestinal perforation
Active diverticulitis
Multi-organ failure as determined by primary treating physicians
Any other documented serious, active infection besides COVID-19 - including but not limited to: lobar pneumonia consistent with bacterial infection, bacteremia, culture-negative endocarditis, or current mycobacterial infection - at the discretion of primary treating physicians
Pregnant patients or nursing mothers
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
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