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

NCT ID: NCT04331795

Last Updated: 2022-06-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-04-04
• Study Completion Date: 2020-06-05

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.

Conditions

COVID-19

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group A

Hospitalized, non-critically ill patients with COVID-19 pneumonitis with risk factors for decompensation

Group Type: EXPERIMENTAL

Tocilizumab

Intervention Type: DRUG

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:

1. Increasing supplemental oxygen requirement or Tmax higher than baseline in the 24h following initial tocilizumab administration AND

2. CRP decrease is < 25% at 24 hours following tocilizumab administration and CRP > 40mg/L

Group B

Hospitalized, non-critically ill patients with COVID-19 pneumonitis without risk factors for decompensation

Group Type: EXPERIMENTAL

Tocilizumab

Intervention Type: DRUG

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:

1. Increasing supplemental oxygen requirement or Tmax higher than baseline in the 24h following initial tocilizumab administration AND

2. CRP decrease is < 25% at 24 hours following tocilizumab administration and CRP > 40mg/L

Interventions

Tocilizumab

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:

1. Increasing supplemental oxygen requirement or Tmax higher than baseline in the 24h following initial tocilizumab administration AND

2. CRP decrease is < 25% at 24 hours following tocilizumab administration and CRP > 40mg/L

Intervention Type: DRUG

Tocilizumab

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:

1. Increasing supplemental oxygen requirement or Tmax higher than baseline in the 24h following initial tocilizumab administration AND

2. CRP decrease is < 25% at 24 hours following tocilizumab administration and CRP > 40mg/L

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Chicago

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pankti Reid, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Chicago, Department of Medicine, Section of Rheumatology

Locations

University of Chicago Medicine

Chicago, Illinois, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 33210302 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB20-0515

Identifier Type: -

Identifier Source: org_study_id