A Study to Evaluate the Efficacy and Safety of Remdesivir Plus Tocilizumab Compared With Remdesivir Plus Placebo in Hospitalized Participants With Severe COVID-19 Pneumonia

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of combination therapy with remdesivir plus tocilizumab compared with remdesivir plus placebo in hospitalized patients with COVID-19 pneumonia.

Official Title
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A Phase III, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir Plus Tocilizumab Compared With Remdesivir Plus Placebo in Hospitalized Patients With Severe COVID-19 Pneumonia

Conditions
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COVID-19 Pneumonia

Intervention / Treatment
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* Drug: Remdesivir
* Drug: Tocilizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Hospitalized with COVID-19 pneumonia confirmed per a positive polymerase chain reaction (PCR) of any specimen (e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT scan Requiring more than 6 L/min supplemental oxygen to maintain SpO2 > 93% Agrees to not participate in another clinical trial for the treatment of COVID-19 while participating in this study Exclusion Criteria Known severe allergic reactions to tocilizumab or other monoclonal antibodies Known hypersensitivity to remdesivir, the metabolites, or formulation excipients 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 Treatment with immunosuppressive or immunomodulatory therapy (including tocilizumab) within the past 3 months Concurrent treatment with other agents with actual or possible direct-acting antiviral activity against SARS-CoV-2 within 24 hours prior to study drug dosing. In addition, participants with prior or current treatment with > 2 doses of remdesivir for COVID-19 are excluded Participating in other drug clinical trials Estimated glomerular filtration rate (eGFR) < 30 mL/min (including patients receiving hemodialysis or hemofiltration) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN) detected within 24 hours of screening (according to local laboratory reference ranges) Absolute neutrophil count (ANC) < 1000/uL at screening Platelet count < 50,000/uL at screening Body weight < 40 kg Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization

Ages Eligible for Study
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Minimum Age: 12 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: Remdesivir + Tocilizumab (RDV+TCZ)<br>Participants assigned to the RDV+TCZ arm will receive a 10-day treatment course of RDV, plus one infusion of TCZ on Day 1. | Drug: Remdesivir<br>* Participants will receive intravenous (IV) RDV<br>Drug: Tocilizumab<br>* Participants will receive IV TCZ<br>|
| Active Comparator: Remdesivir + Placebo (RDV+Placebo)<br>Participants assigned to the RDV+ placebo arm will receive a 10-day treatment course of RDV, plus one infusion of TCZ-placebo on Day 1. | Drug: Remdesivir<br>* Participants will receive intravenous (IV) RDV<br>Drug: Placebo<br>* Participants will receive IV placebo matched to TCZ<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Hospital Discharge or Ready for Discharge up to Day 28 | Defined as days from randomization to hospital discharge or Ready for Discharge not followed by ordinal scale category >1, hospital readmission or death. Hospital discharge or Ready for Discharge is defined as an ordinal score of 1 on the 7-point ordinal scale. Participants who die are censored at Day 28. Discharged (or ready for discharge as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) Death | Up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Mechanical Ventilation or Death up to Day 28 | Time to Mechanical Ventilation or Death defined as the time from randomization to the first occurrence of death or mechanical ventilation. For participants already on mechanical ventilation at baseline, only death is counted as an event. | Up to Day 28 | 
| Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 14 | Clinical status was assessed by the investigator according to the following ordinal scale categories: Discharged (or ready for discharge as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) Death | Day 14 | 
| Time to Death up to Day 28 | Time to death is defined as the time from randomization to death. | Up to Day 28 | 
| Time to Death up to Day 60 | Time to death is defined as the time from randomization to death. | Up to Day 60 | 
| Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-category Ordinal Scale of Clinical Status up to Day 28 | Defined as time from randomization to the time when at least a 2-category improvement in the 7-category ordinal scale is observed. Patients who die are censored at day 28. Clinical status was assessed by the investigator according to the following ordinal scale categories: Discharged (or ready for discharge as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) Death | Up to Day 28 | 
| Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 7 | Clinical status was assessed by the investigator according to the following ordinal scale categories: Discharged (or ready for discharge as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) Death | Day 7 | 
| Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 21 | Clinical status was assessed by the investigator according to the following ordinal scale categories: Discharged (or ready for discharge as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) Death | Day 21 | 
| Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 28 | Clinical status was assessed by the investigator according to the following ordinal scale categories: Discharged (or ready for discharge as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) Death | Day 28 | 
| Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 60 | Clinical status was assessed by the investigator according to the following ordinal scale categories: Discharged (or ready for discharge as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) Death | Day 60 | 
| Proportion of Participants Requiring Initiation of Mechanical Ventilation Post-baseline (Participants Who Did Not Require Mechanical Ventilation at Baseline) | Day 28: Participants who withdraw or die prior to Day 28 are assumed to have required mechanical ventilation. Participants without mechanical ventilation prior to discharge are assumed not to have required mechanical ventilation unless they die by Day 28, which are counted as an event. Day 60: Participants who withdraw or die prior to Day 60 are assumed to have required mechanical ventilation. Participants without mechanical ventilation prior to discharge are assumed not to have required mechanical ventilation unless they die by Day 60, which are counted as an event. | Day 28 and Day 60 | 
| Proportion of Participants Who Are Alive and Free of Respiratory Failure at Day 28 and Day 60 (Participants Requiring Mechanical Ventilation at Baseline) |  | Day 28 and Day 60 | 
| Duration of Mechanical Ventilation (Participants Requiring Mechanical Ventilation at Baseline) up to Day 28 | Participants who die by Day 28 are assigned a duration of 28 days. | Up to Day 28 | 
| Difference in Mortality at Days 14, 28, and 60 |  | Days 14, 28, and 60 | 
| Time to Recovery up to Day 28 | Defined as the time from randomization to the time when an ordinal scale category of 2 (non-ICU hospital ward or ready for hospital ward not requiring supplemental oxygen) or better is observed, not followed by ordinal scale category >2 or death. Participants who die are censored at day 28. Discharged (or ready for discharge as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) Death | Up to Day 28 | 
| Proportion of Participants Who Are Discharged or Ready for Discharge up to Day 28 | Defined as hospital discharge or Ready for Discharge not followed by ordinal scale category >1, hospital readmission or death. Discharged (or ready for discharge as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) Death | Up to Day 28 | 
| Proportion of Participants Who Require Initiation of Mechanical Ventilation Post-baseline or Die up to Day 28 | Participants already on mechanical ventilation at baseline are only counted as an event if death occurs. | Up to Day 28 |