Study in Participants With Early Stage Coronavirus Disease 2019 (COVID-19) to Evaluate the Safety, Efficacy, and Pharmacokinetics of Remdesivir Administered by Inhalation

Study Overview
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Brief Summary
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The primary objective of this study is to characterize the impact of inhaled remdesivir (RDV) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in participants with early stage coronavirus disease 2019 (COVID-19).

Detailed Description
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This study will have multiple parts: Part A, Part B, and Part C. Part B will be conducted if supported by evaluation in healthy volunteers in another Phase 1a Gilead study (GS-US-553-9018). Participants in Part C will be enrolled after review of preliminary safety and available efficacy data from Parts A and B through at least Day 7. GS-US-553-9018 is a Phase 1a randomized, blinded, placebo-controlled, single- and multiple-dose study in healthy volunteers to evaluate the safety, tolerability, and pharmacokinetics of remdesivir administered by inhalation.

Official Title
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A Phase 1b/2a Study in Participants With Early Stage COVID-19 to Evaluate the Safety, Efficacy, and Pharmacokinetics of Remdesivir Administered by Inhalation

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Remdesivir (RDV)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Willing and able to provide written informed consent, or with a legal representative who can provide informed consent SARS-CoV-2 infection first confirmed by polymerase chain reaction (PCR) (Parts A and B) or by nucleic acid testing or direct antigen testing (Part C) with sample collected ≤ 4 days prior to randomization COVID-19 symptom onset ≤ 7 days prior to randomization Oxygen saturation as measured by pulse oximetry (SpO2) > 94% on room air Key Exclusion Criteria: Ongoing or prior participation in any other clinical trial of an experimental vaccine or treatment for COVID-19 Prior or current hospitalization for COVID-19 or need for hospitalization Treatment of COVID-19 with other agents with actual or possible direct antiviral activity against SARS-CoV-2 including intravenous (IV) RDV or administration of any SARS-CoV-2 (or COVID-19) vaccine Participants chronically administered chloroquine or hydroxychloroquine for any reason are to be excluded Requiring oxygen supplementation Positive pregnancy test Breastfeeding female Known hypersensitivity to the study treatment, its metabolites, or formulation excipient Pre-existing pulmonary conditions such as chronic obstructive pulmonary disease or asthma (Parts A and B only) Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Remdesivir (RDV), Part A<br>Participants will receive inhaled RDV 31 mg administered daily for 5 days. | Drug: Remdesivir (RDV)<br>* Administered as an aerosolized solution<br>* Other names: GS-5734™;|
| Experimental: RDV + Placebo, Part A<br>Participants will receive inhaled RDV 31 mg administered daily for 3 days followed by placebo to match RDV daily for 2 days. | Drug: Remdesivir (RDV)<br>* Administered as an aerosolized solution<br>* Other names: GS-5734™;Drug: Placebo<br>* Administered as an aerosolized solution<br>|
| Placebo Comparator: Placebo, Part A<br>Participants will receive placebo to match inhaled RDV in Part A daily for 5 days. | Drug: Placebo<br>* Administered as an aerosolized solution<br>|
| Experimental: RDV, Part B<br>Participants will receive inhaled RDV 62 mg administered daily for up to 5 days. | Drug: Remdesivir (RDV)<br>* Administered as an aerosolized solution<br>* Other names: GS-5734™;|
| Experimental: RDV + Placebo, Part B<br>Participants will receive inhaled RDV 62 mg administered daily for up to 3 days followed by placebo to match RDV daily for 2 days. | Drug: Remdesivir (RDV)<br>* Administered as an aerosolized solution<br>* Other names: GS-5734™;Drug: Placebo<br>* Administered as an aerosolized solution<br>|
| Placebo Comparator: Placebo, Part B<br>Participants will receive placebo to match inhaled RDV in Part B daily for 5 days. | Drug: Placebo<br>* Administered as an aerosolized solution<br>|
| Experimental: RDV, Part C<br>Participants will receive inhaled RDV 39 mg administered daily for 5 days. | Drug: Remdesivir (RDV)<br>* Administered as an aerosolized solution<br>* Other names: GS-5734™;|
| Placebo Comparator: Placebo, Part C<br>Participants will receive placebo to match inhaled RDV in Part C daily for 5 days. | Drug: Placebo<br>* Administered as an aerosolized solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-weighted Average Change From Baseline in Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Load Through Day 7 | Time-weighted average change in SARS-CoV-2 viral load was defined as area under the concentration versus time curve (AUC) of viral load change divided by time between baseline through Day 7. | Baseline, Day 7 | 
| Time-weighted Average Change From Baseline in Oropharyngeal SARS-CoV-2 Viral Load Through Day 7 | Time-weighted average change in SARS-CoV-2 viral load was defined as AUC of viral load change divided by time between baseline through Day 7. | Baseline, Day 7 | 
| Time-weighted Average Change From Baseline in Saliva SARS-CoV-2 Viral Load Through Day 7 | Time-weighted average change in SARS-CoV-2 viral load was defined as AUC of viral load change divided by time between baseline through Day 7. | Baseline, Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a participant administered a study drug, which did not necessarily have a causal relationship with the treatment. AE was therefore any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. TEAEs: AE with an onset date on or after the study drug start date and no later than 30 days after study drug stop date; or any AE leading to study drug discontinuation. | First dose date up to 5 days plus 30 days | 
| Percentage of Participants With Treatment-Emergent Laboratory Abnormalities as Per Severity Grade | Treatment-emergent laboratory abnormalities were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 July 2017. Laboratory abnormalities were graded as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening). Percentage of participants with any severity grade were reported. | First dose date up to 5 days plus 30 days | 
| Percentage of Participants With Treatment-Emergent Adverse Events Leading to Study Treatment Discontinuation |  | First dose date up to 5 days plus 30 days | 
| Number of Participants With All-Cause Medically Attended Visits (MAVs) or Death by Day 28 | The composite outcome of all-cause MAVs (medical visits attended in person by the participant and a health care professional) or all-cause death by Study Day 28 were estimated using Kaplan-Meier methods by treatment group. | Randomization up to Day 28 | 
| Number of Participants With COVID-19 Related MAVs or Death by Day 28 | The composite outcome of COVID-19 related MAVs (medical visits attended in person by the participant and a health care professional) or all-cause death by Study Day 28 were estimated using Kaplan-Meier methods by treatment group. | Randomization up to Day 28 | 
| Number of Participants With Hospitalization by Day 28 | The composite of all-cause hospitalization was estimated using Kaplan-Meier methods by treatment group. | Day 1 up to Day 28 | 
| Pharmacokinetic (PK) Parameter: AUC0-24h of Remdesivir (RDV) and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | AUC0-24h was defined as the concentration of drug over time between time 0 to time 24 hours. Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: AUClast of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | AUClast was defined as the concentration of drug from time zero to the last observable concentration.Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: CLss/F of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | CLss/F was defined as apparent oral clearance at steady state after administration of the drug. CLss/F = Dose/AUCtau, where Dose is the dose of the drug. Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: t1/2 of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | t1/2 was defined as the estimate of the terminal elimination half-life of the drug. Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: Vz/F of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | Vz/F was defined as the apparent volume of distribution of the drug. Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: Cmax of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | Cmax was defined as the maximum observed concentration of drug.Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: Tmax of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | Tmax was defined as the time (observed time point) of Cmax. Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: Clast of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | Clast was defined as the last observable concentration of drug. Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: Tlast of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | Tlast was defined as the time (observed time point) of Clast. Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: AUCtau of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | AUCtau is defined as concentration of drug over time (the area under the concentration versus time curve over the dosing interval). Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: λz of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | λz was defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| PK Parameter: Ctau of RDV and Its Metabolites (GS-441524 and GS-704277) in Parts A and B | Ctau was defined as the observed drug concentration at the end of the dosing interval. Time Frame for PK samples: Sparse PK (all participants): Day 1 (end of nebulization, and optional 2-hour post nebulization), and Day 3 (predose and end of nebulization); Intensive PK (Up to 6 participants/group in Part A & Part B): Day 1 and an additional sample at Day 3 or Day 5 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization. | Sparse PK: Day 1 (end of nebulization) and Day 3 (predose and end of nebulization); Intensive PK: Day 1 and Day 3 or Day 5 (0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 24 hours post end of nebulization); Nebulization duration: 17-34 minutes. | 
| Change in Nasopharyngeal SARS-CoV-2 Viral Load From Baseline to Day 5 |  | Baseline, Day 5 | 
| Change in Oropharyngeal SARS-CoV-2 Viral Load From Baseline to Day 5 |  | Baseline, Day 5 | 
| Change in Saliva SARS-CoV-2 Viral Load From Baseline to Day 5 |  | Baseline, Day 5 | 
| Change in Nasopharyngeal SARS-CoV-2 Viral Load From Baseline to Day 7 |  | Baseline, Day 7 | 
| Change in Oropharyngeal SARS-CoV-2 Viral Load From Baseline to Day 7 |  | Baseline, Day 7 | 
| Change in Saliva SARS-CoV-2 Viral Load From Baseline to Day 7 |  | Baseline, Day 7 | 
| Change in Nasopharyngeal SARS-CoV-2 Viral Load From Baseline to Day 14 in Parts A and B |  | Baseline, Day 14 | 
| Change in Oropharyngeal SARS-CoV-2 Viral Load From Baseline to Day 14 in Parts A and B |  | Baseline, Day 14 | 
| Change in Saliva SARS-CoV-2 Viral Load From Baseline to Day 14 in Parts A and B |  | Baseline, Day 14 | 
| Time to Negative Nasopharyngeal SARS-CoV-2 Polymerase Chain Reaction (PCR) | The time to negative nasopharyngeal SARS-CoV-2 PCR was defined as the number of days to first confirmed negative (first date of two consecutive dates achieving negative result) using nasopharyngeal sample. Time to negative nasopharyngeal SARS-CoV-2 PCR was calculated using Kaplan-Meier estimates. | Baseline up to Day 17 | 
| Time to Negative Oropharyngeal SARS-CoV-2 Polymerase Chain Reaction (PCR) | The time to negative oropharyngeal SARS-CoV-2 PCR was defined as the number of days to first confirmed negative (first date of two consecutive dates achieving negative result) using an oropharyngeal sample. Time to negative oropharyngeal SARS-CoV-2 PCR was calculated using Kaplan-Meier estimates. | Baseline up to Day 17 | 
| Time to Negative Saliva SARS-CoV-2 Polymerase Chain Reaction (PCR) | The time to saliva SARS-CoV-2 PCR was defined as the number of days to first confirmed negative (first date of two consecutive dates achieving negative result) using saliva sample. Time to negative saliva SARS-CoV-2 PCR was calculated using Kaplan-Meier estimates. | Baseline up to Day 17 | 
| Time to Alleviation (Mild or Absent) of Baseline COVID-19 Symptoms as Reported on the COVID-19 Adapted InFLUenza Patient-Reported Outcome (FLU-PRO©) Questionnaire in Part C | The InFLUenza Patient-Reported Outcome (FLU-PRO©) is a 32-item patient-reported outcome questionnaire that assesses the severity of symptoms of influenza and influenza-like illness across six body systems. An additional two items can be added to assess changes in taste or smell, if the instrument is used to quantify symptoms in studies of COVID-19. Each domain scores ranges from 0 (symptom-free) to 4 (very severe symptoms). Higher scores on this scale represent higher disease severity. Alleviation is defined as symptom scores as 2 or higher at baseline are scored as 0 (absent) or 1 (mild) at post-baseline, and symptoms scored as 1 at baseline are scored as 0 at post-baseline, and for two consecutive days. Time to alleviation was calculated using Kaplan-Meier estimates. | First dose date up to Day 14 |