A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of tocilizumab (TCZ) compared with a matching placebo in combination with standard of care (SOC) in hospitalized patients with severe COVID-19 pneumonia.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia

Conditions
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COVID-19 Pneumonia

Intervention / Treatment
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* Drug: Tocilizumab (TCZ)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT scan SPO2 </=93% or PaO2/FiO2 <300 mmHg Exclusion Criteria: Known severe allergic reactions to TCZ or other monoclonal antibodies Active tuberculosis (TB) infection Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments Have received oral anti-rejection or immunomodulatory drugs (including TCZ) with the past 3 months Participating in other drug clinical trials (participation in COVID-19 anti-viral trials may be permitted if approved by Medical Monitor) Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization (investigational COVID-19 antivirals may be permitted if approved by Medial Monitor) Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 10 x upper limit of normal (ULN) detected within 24 hours at screening (per local lab) Absolute neutrophil count (ANC) < 1000/mL at screening (per local lab) Platelet count < 50,000/mL at screening (per local lab)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab (TCZ) Arm<br>Participants will receive 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement. | Drug: Tocilizumab (TCZ)<br>* Participants will receive 1 dose of IV TCZ. 1 additional dose may be given if clinical symptoms worsen or show no improvement.<br>|
| Placebo Comparator: Placebo Arm<br>Participants will receive 1 IV infusion of placebo matched to TCZ. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement. | Drug: Placebo<br>* Participants will receive 1 dose of IV placebo matched to TCZ. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 28 (Week 4) | Clinical status was assessed using a 7-category ordinal scale: - Discharged (or ready for discharge) - Non- intensive care unit (ICU) hospital ward (or ready for hospital ward) not requiring supplemental oxygen - Non-ICU hospital ward (or ready for hospital ward) requiring supplemental oxygen - ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen - ICU, requiring intubation and mechanical ventilation - ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support - Death | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Clinical Improvement (TTCI), Defined as a National Early Warning Score 2 (NEWS2) of </= 2 Maintained for 24 Hours | Defined as time from first dose of study drug to at least two NEWS2 assessments with a score of <=2 covering a span of at least 21.5 hours, with a maximum of 26.5 hours between the first and last of these assessments and no assessments with a score >2 in between. If one of the components of the NEWS2 score was missing at a particular time point, then the NEWS2 score was not calculated. Participants who died were censored at Day 28. | Up to Day 28 | 
| Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status | Time to improvement for this outcome measure was defined as the days from the first dose of study drug to when at least a 2-category improvement in clinical status (based on a 7-category ordinal scale) is observed. Participants who died were censored at Day 28. | Up to Day 28 | 
| Time to Hospital Discharge or Ready for Discharge | Time to Hospital Discharge was defined as the time from the first dose of study drug to hospital discharge or ready for discharge (normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or </=2L supplemental oxygen) Participants who died were censored at Day 28. | Up to Day 28 | 
| Incidence of Mechanical Ventilation by Day 28 | Participants who died by Day 28 were assumed to have required mechanical ventilation. | Up to Day 28 | 
| Ventilator-Free Days to Day 28 | Participants who died by Day 28 were assigned 0 ventilator-free days. | Up to Day 28 | 
| Incidence of Intensive Care Unit (ICU) Stay by Day 28 (Week 4) | Participants who died by Day 28 were assumed to have required an ICU stay. | Up to Day 28 | 
| Duration of ICU Stay to Day 28 (Week 4) | Participants who died by Day 28 were assigned a duration from the first dose of study drug to Day 28 at hour 23:59:59. | Up to Day 28 | 
| Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 14 | Clinical status was assessed using a 7-category ordinal scale: - Discharged (or ready for discharge) - Non- intensive care unit (ICU) hospital ward (or ready for hospital ward) not requiring supplemental oxygen - Non-ICU hospital ward (or ready for hospital ward) requiring supplemental oxygen - ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen - ICU, requiring intubation and mechanical ventilation - ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support - Death | Day 14 | 
| Time to Clinical Failure to Day 28 (Week 4) | Time to clinical failure was defined as the number of days from the first dose of study drug to the first occurrence on study of death, mechanical ventilation, ICU admission, or study withdrawal prior to discharge, whichever occurs first. | Up to Day 28 | 
| Mortality Rate at Day 28 (Week 4) |  | Day 28 | 
| Time to Recovery to Day 28 (Week 4) | Time to recovery was defined as the number of days from the first dose of study drug to hospital discharge or ready for discharge (normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) or non-ICU hospital ward or ready for hospital ward not requiring supplemental oxygen. Participants who died were censored at Day 28. | Up to Day 28 | 
| Duration of Supplemental Oxygen to Day 28 (Week 4) | Participants who died by Day 28 were assigned a duration of 28 days of supplemental oxygen. | Up to Day 28 |