Clinical trial NCT04479358: Low-dose Tocilizumab Versus Standard of Care in Hospitalized Patients With COVID-19
Official title: COVIDOSE-2: A Multi-center, Randomized, Controlled Phase 2 Trial Comparing Early Administration of Low-dose Tocilizumab to Standard of Care in Hospitalized Patients With COVID-19 Pneumonitis Not Requiring Invasive Ventilation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: COVID-19
Keywords: COVID-19
Tocilizumab
Lead sponsor: University of Chicago
Sponsor class: OTHER
First posted: 2020-07-21
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two sub-studies in parallel, each of three arms (maximum).
Primary purpose: TREATMENT

Brief 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.

Detailed 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 EMA- and 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to Recovery
timeFrame: 28 days
Secondary outcomes:
measure: Achievement of Recovery
timeFrame: 7 days
measure: Overall Survival
timeFrame: 28 days
measure: Hospital Length of Stay
timeFrame: Up to 1 year
measure: Clinical Response: Maximum Temperature (Tmax) Response
timeFrame: 24 hours
measure: Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation
timeFrame: Up to 28 days
measure: Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation
timeFrame: Up to 28 days
measure: Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation
timeFrame: Up to 28 days
measure: Clinical Response: Rate of Vasopressor/Inotrope Utilization
timeFrame: Up to 28 days
measure: Clinical Response: Duration of Vasopressor/Inotrope Utilization
timeFrame: Up to 28 days
measure: Clinical Response: Time to Vasopressor/Inotrope Utilization
timeFrame: Up to 28 days
measure: Clinical Response: Duration of Increased Supplemental Oxygen From Baseline
timeFrame: 28 days
measure: Biochemical Response: C-reactive Protein Response Rate
timeFrame: 24 hours
measure: Safety: Rate of Secondary Infection
timeFrame: 28 days
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
Study officials:
affiliation: University of Chicago
name: Pankti D Reid, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Strohbehn GW, Reid PD, Ratain MJ. Applied Clinical Pharmacology in a Crisis: Interleukin-6 Axis Blockade and COVID-19. Clin Pharmacol Ther. 2020 Sep;108(3):425-427. doi: 10.1002/cpt.1931. Epub 2020 Jul 4.