Tocilizumab in Coronavirus-19 Positive Patients

Phase 3

• Conditions: Severe Acute Respiratory Syndrome Coronavirus 2; Covid19; Inflammation; COVID-19; Coronavirus
• Interventions: Biological: Tocilizumab

• Registration Number: NCT04423042
• Lead Sponsor: University of Calgary

Brief Summary

This is a cohort study of COVID-19 patients with hyperinflammation. It aims to determine the impact of adjunctive Tocilizumab (TCZ) to standard of care on the reduction of hyperinflammation-related mortality in COVID-19. Patients with COVID-19 are at high risk of life-threatening hyperinflammation and death. One in three COVID-19 patients admitted to ICU was found to develop life-threatening hyperinflammation. The risk of death when untreated is estimated to be 50-80%.

Detailed Description

The novel coronavirus, SARS-Cov2/COVID-19, emerged in late 2019 in Wuhan, China. Quickly, SARS-CoV2 spread to all corners of the globe. In March 2020, The World Health Organization (WHO) declared SARS-CoV2/COVID-19 a pandemic. Individuals infected with SARS-CoV2 have a varied clinical presentation, ranging from asymptomatic or mild respiratory symptoms to severe involvement of the lower respiratory tract, with patients requiring mechanical ventilation. A particular point of interest is how the overall severity and clinical outcomes of COVID-19 patients may be associated with the excessive production of pro-inflammatory cytokines, or hyperinflammation, leading to acute respiratory distress syndrome. This state of hyperinflammation may be associated with increased mortality in COVID-19 patients. Tocilizumab, an Interleukin-6 antagonist, may help treat COVID-19 associated hyperinflammation.

This is a nested interventional cohort study of COVID-19 patients with hyperinflammation. It aims to determine the impact of adjunctive Tocilizumab (TCZ) to standard of care on the reduction of hyperinflammation-related mortality in COVID-19. Patients with COVID-19 are at high risk of life-threatening hyperinflammation and death. One in three COVID-19 patients admitted to ICU was found to develop life-threatening hyperinflammation. The risk of death when untreated is estimated to be 50-80%. TCZ treatment may reduce mortality.

Primary objective: To establish that tocilizumab, in addition to standard of care, reduces the 30-day mortality from hyperinflammation in COVID-19 disease significantly compared to no anti-interleukin therapy plus standard of care.

Secondary objectives: To evaluate the addition of tocilizumab therapy to standard of care on a number of secondary outcomes.

Study Timeline

• Study First Submitted: 2020-06-05
• Study First Submitted QC: 2020-06-05
• Study First Posted: 2020-06-09
• Status Verified: 2020-07
• Last Update Submitted: 2020-07-20
• Last Update Posted: 2020-07-22
• Study Start: 2020-07-30
• Primary Completion: 2021-06
• Study Completion: 2021-06

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

1. Age ≥ 18 years

2. All genders

3. Hospitalization for suspected or confirmed SARS-CoV2 infection. COVID-19 diagnosis defined as positive on reverse-transcriptase polymerase chain reaction, with provincial laboratory confirmation.

4. Signs of hyperinflammation (cytokine release syndrome) defined by the presence of any of the following:

   i. Elevated C-reactive protein (≥70 mg/dl and/or rising since last 24h not due to bacterial infection), ii. Ferritin (>700 mcg/L and/or rising since last 24h),

5. Anti-interleukin treatment indication as per hyperinflammation team

6. Informed consent for participation in the study

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Exclusion Criteria

1. Goal of Care C (palliative care)
2. Known hypersensitivity to TCZ or its components
3. Current systemic immunosuppressive therapy; anti-interleukin 1 or anti-interleukin 6 treatment
4. Known active bacterial or fungal infections or other clinical conditions that contraindicate TCZ and cannot be treated or resolved according to the physician's judgment
5. Current or history of bowel perforation or diverticulitis
6. Suspicion of active or latent tuberculosis
7. Pregnant or breastfeeding patient
8. Patients with known prior liver disease

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tocilizumab Arm	Tocilizumab	Tocilizumab 8 mg/kg IV up to a maximum of 800 mg with possible repetition of the same dosage within 28 hours (the optional second dose after 12 hours but before 28 hours following the first dose), based on the clinical judgement of the attending physician in consultation with the COVID-inflammation team.

Primary Outcome Measures

Name	Time	Method
All-cause mortality	Assessed at 30 days post treatment	Mortality status of participants

Secondary Outcome Measures

Name	Time	Method
Ordinal Scale for evaluating subject clinical status at days 3, 8, 15, 30, 60 post treatment.	Assessed at days 3, 8, 15, 30, 60 post treatment	Uninfected, ambulatory, hospitalized: mild disease, hospitalized: severe disease, death