Study to Evaluate the Efficacy and Safety of Remdesivir in Participants With Severely Reduced Kidney Function Who Are Hospitalized for Coronavirus Disease 2019 (COVID-19)

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate whether remdesivir (RDV, GS-5734™) reduces the composite risk of death or invasive mechanical ventilation (IMV) through Day 29 in participants with severely reduced kidney function who are hospitalized for coronavirus disease 2019 (COVID-19).

Official Title
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A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study Evaluating the Efficacy and Safety of Remdesivir in Participants With Severely Reduced Kidney Function Who Are Hospitalized for COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Remdesivir
* Drug: RDV Placebo
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) positive as determined by Polymerase Chain Reaction (PCR) or other commercially available or public health assay (eg, Nucleic Acid Amplification Test (NAAT) and antigen tests) in any respiratory specimen Hospitalized for COVID-19 Weighing at least 40 kilograms (kg) Oxygen (O2) saturation ≤ 94% on room air or requiring O2 supplement or Radiographic evidence of pulmonary infiltrates for COVID-19 Have either: a) Severely reduced kidney function (estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m^2), including people with end-stage kidney disease (ESKD) requiring chronic dialysis b) Ongoing acute kidney injury (AKI): defined as a 50% increase in serum creatinine (SCr) within a 48-hour period that is sustained (ie, requires confirmatory SCr) for ≥ 6 hours despite supportive care The interval between COVID-19 symptoms onset and randomization is no more than 10 days Key Exclusion Criteria: Received any investigational drug, RDV, or other antiviral treatment for COVID-19 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limit of normal Invasive mechanical ventilation, noninvasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), or renal replacement therapy (RRT) for acute kidney injury (AKI) Positive serum pregnancy test at screening for women of childbearing potential or currently breastfeeding Known hypersensitivity to the study drug, metabolites, or formulation sulfobutylether-beta-cyclodextrin (SBECD) Note: Other protocol defined Inclusion/Exclusion criteria may apply

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 (RDV)<br>Participants will receive continued Standard of Care (SOC) therapy together with RDV 200 mg on Day 1 followed by RDV 100 mg from Day 2 up to Day 5. | Drug: Remdesivir<br>* Administered as Intravenous (IV) infusion once daily<br>* Other names: Veklury®;Drug: Standard of Care<br>* Standard of Care Treatment for COVID-19 Infection<br>|
| Placebo Comparator: Placebo<br>Participants will receive continued SOC therapy together with RDV matching placebo on Day 1 followed by RDV matching placebo from Day 2 up to Day 5. | Drug: RDV Placebo<br>* Administered as IV saline once daily<br>Drug: Standard of Care<br>* Standard of Care Treatment for COVID-19 Infection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With All-cause Death or Invasive Mechanical Ventilation (IMV) Through Day 29 | This is the combined outcome measure reporting the percentage of participants with all-cause death or IMV through Day 29. The reported percentage was from the Kaplan-Meier estimate. | First dose date up to Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause Mortality Through Day 29 | The reported percentage was from the Kaplan-Meier estimate. | First dose date up to Day 29 | 
| Percentage of Participants With Initiation of IMV Through Day 29 | The reported percentage was the cumulative-incidence estimate. | First dose date up to Day 29 | 
| Time to Recovery Without Subsequent Worsening (Defined as an Ordinal Scale Score of > 4) by Day 29 | Time to recovery is the time from first dose to recovery. Recovery is defined as the first day on which the participant with a baseline score ≥ 4, satisfies categories 1, 2, or 3 from the 8-point ordinal scale: 1) Non-hospitalized, no limitations on activities; 2) Non-hospitalized, limitations on activities/requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care for COVID-19; 5) Hospitalized, supplemental oxygen; 6) Hospitalized, on noninvasive ventilation; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death. Cumulative incidence was reported. | First dose date up to Day 29 | 
| Time to Recovery Independent of Further Worsening by Day 29 | Time to recovery is the time from first dose to recovery. Recovery is defined as the first day on which the participant with a baseline score ≥ 4, satisfies categories 1, 2, or 3 from the 8-point ordinal scale: 1) Non-hospitalized, no limitations on activities; 2) Non-hospitalized, limitations on activities/requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care for COVID-19; 5) Hospitalized, supplemental oxygen; 6) Hospitalized, on noninvasive ventilation; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 8) Death. Cumulative incidence was reported. | First dose date up to Day 29 | 
| Percentage of Participants Within Each Clinical Status Category as Assessed by an 8-Point Ordinal Scale on Day 15 | Clinical status is derived from death, hospital discharge, and the ordinal scale. Each day, the worst (highest) score from the previous day was recorded. The 8-point Ordinal scale is as follows: 1. Not hospitalized, no limitations on activities; 2. Not hospitalized, limitation on activities and/or requiring home oxygen; 3. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than per-protocol RDV/saline as placebo administration); 4. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care for COVID-19-specific medical care (other than per-protocol RDV administration); 5. Hospitalized, supplemental oxygen; 6. Hospitalized, on noninvasive ventilation or high-flow oxygen devices; 7. Hospitalized, on IMV or ECMO; and 8. Death. Higher scores indicate worse clinical status. | Day 15 | 
| Percentage of Participants Within Each Clinical Status Category as Assessed by an 8-Point Ordinal Scale on Day 29 | Clinical status is derived from death, hospital discharge, and the ordinal scale. Each day, the worst (highest) score from the previous day was recorded. The 8-point Ordinal scale is as follows: 1. Not hospitalized, no limitations on activities; 2. Not hospitalized, limitation on activities and/or requiring home oxygen; 3. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than per-protocol RDV/saline as placebo administration); 4. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care for COVID-19-specific medical care (other than per-protocol RDV administration); 5. Hospitalized, supplemental oxygen; 6. Hospitalized, on noninvasive ventilation or high-flow oxygen devices; 7. Hospitalized, on IMV or ECMO; and 8. Death. Higher scores indicate worse clinical status. | Day 29 | 
| Renal Replacement Therapy (RRT)-Free Days (Among Those Without End-Stage Kidney Disease [ESKD] at Baseline) Through Day 29 | The number of RRT free days were calculated as the number of full days from Day 1 to Day 29 on which the participant was alive and did not receive RRT. | First dose date up to Day 29 | 
| Percentage of Participants With Recovery Without Subsequent Worsening (Defined as an Ordinal Scale Score of > 4) Through Day 29 | Recovery is defined as the first day on which the participant with a baseline score >= 4, satisfies categories 1, 2, or 3 from the 8-point ordinal scale including: 1) Non-hospitalized, no limitations on activities; 2) Non-hospitalized, limitations on activities/requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care for COVID-19; 5) Hospitalized, supplemental oxygen; 6) Hospitalized, on noninvasive ventilation; 7) Hospitalized, on IMV or ECMO; 8) Death. | First dose date up to Day 29 | 
| Percentage of Participants With Recovery Independent of Further Worsening Through Day 29 | Recovery is defined as the first day on which the participant with a baseline score >= 4, satisfies categories 1, 2, or 3 from the 8-point ordinal scale including: 1) Non-hospitalized, no limitations on activities; 2) Non-hospitalized, limitations on activities/requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care for COVID-19; 5) Hospitalized, supplemental oxygen; 6) Hospitalized, on noninvasive ventilation; 7) Hospitalized, on IMV or ECMO; 8) Death. | First dose date up to Day 29 | 
| Percentage of Participants Experiencing Serious Adverse Events (SAEs) | An SAE was defined as an event that, at any dose, results in the following: Death, a life-threatening situation, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect, a medically important event or reaction which may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require intervention to prevent one of the other outcomes constituting SAEs. | First dose date up to last dose date (Maximum: 5 days) plus 30 days | 
| Percentage of Participants Who Permanently Discontinued Investigational Drug Due to Adverse Events (AEs) | An AE is any untoward medical occurrence in a clinical study participant administered an investigational drug, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of an investigational drug, whether or not the AE is considered related to the investigational drug. | First dose date up to last dose date (Maximum: 5 days) |