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

Primary Purpose

COVID-19

Status

Active

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Tocilizumab

Standard of Care

About this trial

This is an interventional treatment trial for COVID-19 focused on measuring COVID-19, Tocilizumab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of Chicago Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Active Comparator

Experimental

Active Comparator

Experimental

Arm Label

Sub-study A, Tocilizumab-Free Standard of Care

Sub-study A, Tocilizumab 40mg

Sub-study A, Tocilizumab 120mg

Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care

Sub-study B, Tocilizumab 40mg

Sub-study B, Tocilizumab 120mg

Arm Description

Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab.

Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg.

Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg.

Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg).

Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg.

Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg.

Outcomes

Primary Outcome Measures

Time to Recovery

Day of recovery is defined as the first day on which the patient achieves one of the following two categories from the seven-point ordinal scale: 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care or 7) Not hospitalized. Time to recovery is the number of days from randomization to achievement of this status. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.

Secondary Outcome Measures

Achievement of Recovery

This will be defined as the percentage of patients in a given arm of the study achieving one of the above two categories on the ordinal scale on day 7. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.

Overall Survival

This will be defined as the percentage of patients in a given arm of the study who are alive thirty days following randomization. Patients who are discharged to hospice will be counted as deceased on the day of discharge. Patients who are transitioned to inpatient hospice or inpatient comfort measures only will be counted as deceased on the day of transition.

Hospital Length of Stay

This will be defined as the number of days that pass between the day of a patient's randomization and his or her discharge from the hospital.

Clinical Response: Maximum Temperature (Tmax) Response

Maximum temperature within 24-hour periods of time immediately prior to, immediately following, and then every 24 hours thereafter randomization. The primary endpoint is a measured Tmax in the 24-hour period immediately following randomization that is lower than the measured Tmax in the 24-hour period immediately preceding randomization.

Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation

This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of invasive mechanical ventilation during the course of the patient's COVID-19 infection.

Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation

This will be a continuous outcome defined by the amount of time between initiation and cessation of non-elective invasive mechanical ventilation.

Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation

This will be a continuous outcome defined by the amount of time between randomization and the initiation of non-elective invasive mechanical ventilation. This will be treated as a time-to-event with possible censoring.

Clinical Response: Rate of Vasopressor/Inotrope Utilization

This will be a binary outcome defined as utilization of any vasopressor or inotropic medication.

Clinical Response: 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 medications.

Clinical Response: Time to Vasopressor/Inotrope Utilization

This will be a continuous outcome defined by the amount of time between randomization and the initiation of any vasopressor or inotropic medication. This will be treated as a time-to-event with possible censoring.

Clinical Response: Duration of Increased Supplemental Oxygen from Baseline

This will be an ordinal outcome defined by the number of days counted from randomization over which the participant requires supplemental oxygen in excess over 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.

Biochemical Response: C-reactive Protein Response Rate

This will be a binary outcome defined as the presence or absence of a decline in CRP of ≥ 25% from baseline CRP in the 27 +/- 3 hours after tocilizumab administration, as compared to pre-treatment baseline.

Safety: Rate of Secondary Infection

This will be defined as the percentage of patients in a study arm who develop serious non-COVID-19 viral, bacterial, or fungal infections (e.g., bloodstream infection, hospital-acquired pneumonia, ventilator-associated pneumonia, opportunistic infection) following randomization and up to the 28-day assessment of overall survival.

Full Information

NCT ID

NCT04479358

First Posted

July 13, 2020

Last Updated

May 11, 2023

Sponsor

University of Chicago

1. Study Identification

Unique Protocol Identification Number

NCT04479358

Brief Title

Low-dose Tocilizumab Versus Standard of Care in Hospitalized Patients With COVID-19

Acronym

COVIDOSE-2

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

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

September 10, 2020 (Actual)

Primary Completion Date

March 1, 2024 (Anticipated)

Study Completion Date

March 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Chicago

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

COVID-19

Keywords

COVID-19, Tocilizumab

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Two sub-studies in parallel, each of three arms (maximum).

Masking

None (Open Label)

Allocation

Randomized

Enrollment

75 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sub-study A, Tocilizumab-Free Standard of Care

Arm Type

Active Comparator

Arm Description

Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab.

Arm Title

Sub-study A, Tocilizumab 40mg

Arm Type

Experimental

Arm Description

Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg.

Arm Title

Sub-study A, Tocilizumab 120mg

Arm Type

Experimental

Arm Description

Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg.

Arm Title

Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care

Arm Type

Active Comparator

Arm Description

Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg).

Arm Title

Sub-study B, Tocilizumab 40mg

Arm Type

Experimental

Arm Description

Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg.

Arm Title

Sub-study B, Tocilizumab 120mg

Arm Type

Experimental

Arm Description

Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg.

Intervention Type

Drug

Intervention Name(s)

Tocilizumab

Other Intervention Name(s)

Tocilizumab 40mg

Intervention Description

Tocilizumab 40mg

Intervention Type

Drug

Intervention Name(s)

Tocilizumab

Other Intervention Name(s)

Tocilizumab 120mg

Intervention Description

Tocilizumab 120mg

Intervention Type

Other

Intervention Name(s)

Standard of Care

Intervention Description

Tocilizumab-Free Standard of Care

Intervention Type

Other

Intervention Name(s)

Standard of Care

Intervention Description

Tocilizumab 400mg or 8mg/kg

Primary Outcome Measure Information:

Title

Time to Recovery

Description

Time Frame

28 days

Secondary Outcome Measure Information:

Title

Achievement of Recovery

Description

Time Frame

7 days

Title

Overall Survival

Description

Time Frame

28 days

Title

Hospital Length of Stay

Description

This will be defined as the number of days that pass between the day of a patient's randomization and his or her discharge from the hospital.

Time Frame

Up to 1 year

Title

Clinical Response: Maximum Temperature (Tmax) Response

Description

Time Frame

24 hours

Title

Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation

Description

This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of invasive mechanical ventilation during the course of the patient's COVID-19 infection.

Time Frame

Up to 28 days

Title

Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation

Description

This will be a continuous outcome defined by the amount of time between initiation and cessation of non-elective invasive mechanical ventilation.

Time Frame

Up to 28 days

Title

Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation

Description

Time Frame

Up to 28 days

Title

Clinical Response: Rate of Vasopressor/Inotrope Utilization

Description

This will be a binary outcome defined as utilization of any vasopressor or inotropic medication.

Time Frame

Up to 28 days

Title

Clinical Response: Duration of Vasopressor/Inotrope Utilization

Description

This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor medications.

Time Frame

Up to 28 days

Title

Clinical Response: Time to Vasopressor/Inotrope Utilization

Description

Time Frame

Up to 28 days

Title

Clinical Response: Duration of Increased Supplemental Oxygen from Baseline

Description

Time Frame

28 days

Title

Biochemical Response: C-reactive Protein Response Rate

Description

Time Frame

24 hours

Title

Safety: Rate of Secondary Infection

Description

Time Frame

28 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pankti D Reid, MD, MPH

Organizational Affiliation

University of Chicago

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Chicago Medicine

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60637

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Individual participant data that underlie the results of this article, after de-identification. Sharing period will be 1 month after data are published and available indefinitely thereafter. Researchers who provide methodologically sound proposals for the purposes of achieving stated aims in their proposal will be eligible for data-sharing.

IPD Sharing Time Frame

From 1 month following publication of data. Available indefinitely thereafter.

IPD Sharing Access Criteria

Proposals will need to be sent to study principal investigators. Requestors will need to sign a data access request form. Link to be determined.

Citations:

PubMed Identifier

32488861

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.

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Low-dose Tocilizumab Versus Standard of Care in Hospitalized Patients With COVID-19

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