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

Gilead Sciences156 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

156

Conditions

COVID-19

Interventions

Remdesivir (RDV)DRUG

Administered as an aerosolized solution

PlaceboDRUG

Administered as an aerosolized solution

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (28)

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Day 7

Secondary Outcomes

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.

Time frame: 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.

Data from ClinicalTrials.gov

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The Institute for Liver Health

Mesa, Arizona, United States

The Institute for Liver Health

Tucson, Arizona, United States

Franco Felizarta, MD

Bakersfield, California, United States

Aurora FDRC Inc.

Costa Mesa, California, United States

Elevated Health

Huntington Beach, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

Western Clinical Research

Placentia, California, United States

UC Davis Health/Medical Center

Sacramento, California, United States

Bradenton Research Center, Inc.

Bradenton, Florida, United States

Integrity Clinical Research, LLC

Doral, Florida, United States

...and 18 more locations

Time frame: First dose date up to 5 days plus 30 days

Percentage of Participants With Treatment-Emergent Adverse Events Leading to Study Treatment Discontinuation

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Change in Nasopharyngeal SARS-CoV-2 Viral Load From Baseline to Day 5

Time frame: Baseline, Day 5

Change in Oropharyngeal SARS-CoV-2 Viral Load From Baseline to Day 5

Time frame: Baseline, Day 5

Change in Saliva SARS-CoV-2 Viral Load From Baseline to Day 5

Time frame: Baseline, Day 5

Change in Nasopharyngeal SARS-CoV-2 Viral Load From Baseline to Day 7

Time frame: Baseline, Day 7

Change in Oropharyngeal SARS-CoV-2 Viral Load From Baseline to Day 7

Time frame: Baseline, Day 7

Change in Saliva SARS-CoV-2 Viral Load From Baseline to Day 7

Time frame: Baseline, Day 7

Change in Nasopharyngeal SARS-CoV-2 Viral Load From Baseline to Day 14 in Parts A and B

Time frame: Baseline, Day 14

Change in Oropharyngeal SARS-CoV-2 Viral Load From Baseline to Day 14 in Parts A and B

Time frame: Baseline, Day 14

Change in Saliva SARS-CoV-2 Viral Load From Baseline to Day 14 in Parts A and B

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: First dose date up to Day 14