Study to Evaluate the Effects of AT-527 in Non-Hospitalized Adult Patients With Mild or Moderate COVID-19

Study Overview
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Brief Summary
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This randomized study evaluates the antiviral activity, safety, efficacy and pharmacokinetics of AT-527 versus a placebo in participants with mild or moderate coronavirus disease (COVID-19) who are not hospitalized.

Official Title
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A Phase II Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Antiviral Activity, Safety, Pharmacokinetics, and Efficacy of RO7496998 (AT-527) in Non-Hospitalized Adult Patients With Mild or Moderate COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: AT-527
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Positive SARS-CoV-2 diagnostic test (RT-PCR or rapid antigen test)at screening Has symptoms consistent with mild or moderate COVID-19, as determined by the investigator, with onset ≤5 days prior to randomization Exclusion Criteria: Clinical signs indicative of COVID-19 illness requiring hospitalization, defined as any of the following: shortness of breath at rest, respiratory rate ≥30, heart rate ≥125, peripheral capillary oxygen saturation ≤93% on room air Treatment with a therapeutic agent against SARS-CoV-2 including, but not limited to, other direct acting antivirals, convalescent plasma, monoclonal antibodies against SARS CoV-2, or intravenous immunoglobulin within 3 months or less than 5 drug elimination half-lives (whichever is longer) prior to screening Requirement, in the opinion of the investigator, for any of the prohibited medications during the study Use of hydroxychloroquine or amiodarone within 3 months of screening Pregnant or breastfeeding, or intending to become pregnant during the study or within 30 days after the final dose of AT-527. Women of childbearing potential must have a negative urine pregnancy test result at screening Abnormal laboratory test results at screening Clinically significant abnormal ECG, as determined by the Investigator, at screening Planned procedure or surgery during the study Known allergy or hypersensitivity to study drug or drug product excipients Substance abuse, as determined by the investigator, within 12 months prior to screening Poor peripheral venous access Malabsorption syndrome or other condition that would interfere with enteral absorption Any clinically significant history of epistaxis within the last 3 months and/or history of being hospitalized due to epistaxis of any previous occasion History of anaphylaxis Any uncontrolled serious medical condition or other clinically significant abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive AT-527-matched placebo twice a day (BID) on Days 1-5. | Drug: Placebo<br>* The dose and regimen of the placebo will match that of the respective AT-527 comparator arm.<br>|
| Experimental: AT-527 550 mg (1x550 mg)<br>Participants will receive 550 mg AT-527 (1x550 mg) twice a day (BID) on Days 1-5. | Drug: AT-527<br>* Results from Arm AT-527 500 mg determined the dose and regimen to be used for AT-527 1100 mg.<br>* Other names: RO7496998;|
| Experimental: AT-527 1100 mg (4x275 mg)<br>Participants will receive 1100 mg AT-527 (4x275 mg) twice a day (BID) on Days 1-5. | Drug: AT-527<br>* Results from Arm AT-527 500 mg determined the dose and regimen to be used for AT-527 1100 mg.<br>* Other names: RO7496998;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Amount of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Virus RNA for AT-527 550 mg and Matched Placebo | SARS-CoV-2 virus RNA was measured by reverse-transcription polymerase chain reaction (RT-PCR) from nasopharyngeal (NP) swabs. The change from baseline was estimated from an ANCOVA model with baseline viral load as a covariate. Reported here is the adjusted mean change from baseline. A negative change from baseline indicates an improvement. | Baseline, Day 3, Day 5, Day 7 | 
| Change From Baseline in the Amount of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Virus RNA for AT-527 1100 mg and Pooled Placebo | SARS-CoV-2 virus RNA was measured by reverse-transcription polymerase chain reaction (RT-PCR) from NP swabs. The change from baseline was estimated from an ANCOVA model with baseline viral load as a covariate. Reported here is the adjusted mean change from baseline. A negative change from baseline indicates an improvement. | Baseline, Day 3, Day 5, Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Cessation of SARS-CoV-2 Viral Shedding | Time to cessation of viral shedding was defined as the time between the initiation of any study treatment and the first time when a negative or below the limit of detection RT-PCR test result was obtained. RT-PCR was measured from NP swabs. Median, 25th and 75th percentiles were estimated from the Kaplan-Meier curve. | Up to Day 7 | 
| Time to Sustained Non-Detectable SARS-CoV-2 Virus RNA | Time to sustained non-detectable SARS-CoV-2 virus RNA was defined as the time between the initiation of any study treatment and first time when a negative or below the limit of detection test result by RT-PCR is obtained after which no positive test above or equal to the limit of detection was reported. RT-PCR was measured from NP swabs. Median, 25th and 75th percentiles were estimated from the Kaplan-Meier curve. | Up to Day 7 | 
| Percentage of Participants Positive for SARS-CoV-2 Virus RNA at Specified Timepoints | Reported here is the percentage of participants with a positive virus RNA by RT-PCR test result above or equal to the limit of quantification (LOQ). RT-PCR was measured from NP swabs. | Baseline, Day 3, Day 5, Day 7 | 
| Area Under the Curve (AUC) in the Amount of SARS-CoV-2 Virus RNA | AUC is the amount of SARS-CoV-2 virus RNA from baseline to the last sample timepoint and was calculated using the trapezoidal method. RT-PCR was measured from NP swabs. | Baseline, Day 3, Day 5, Day 7 | 
| Time to Alleviation or Improvement of COVID-19 Symptoms (21.5 Hours) | COVID-19 symptoms were evaluated using the first 12 items in the COVID-19 Symptom Diary, which included the following 12 items: nasal congestion or runny nose, sore throat, cough, shortness of breath, muscle or body aches, fatigue, headache, chills/sweats, feeling hot or feverish, nausea, vomiting, and diarrhea. The symptoms were scored on the 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe).Time to alleviation or improvement is defined as the length of time taken from start of treatment to the point at which all of the following three criteria are met and maintained for a concurrent duration of at least 21.5 hours: new symptoms with a score of 0 or 1; pre- existing and worsened due to COVID-19 symptoms with at least a single category improvement from baseline; pre-existing and not worsened due to COVID-19 symptoms remaining the same or at least a single category improvement from baseline. | Up to 28 Days | 
| Time to Alleviation or Improvement of COVID-19 Symptoms (43 Hours) | COVID-19 symptoms were evaluated using the first 12 items in the COVID-19 Symptom Diary, which included the following 12 items: nasal congestion or runny nose, sore throat, cough, shortness of breath, muscle or body aches, fatigue, headache, chills/sweats, feeling hot or feverish, nausea, vomiting, and diarrhea. The symptoms were scored on the 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe). Time to alleviation or improvement is defined as the length of time taken from start of treatment to the point at which all of the following three criteria are met and maintained for a concurrent duration of at least 43 hours: new symptoms with a score of 0 or 1; pre- existing and worsened due to COVID-19 symptoms with at least a single category improvement from baseline; pre-existing and not worsened due to COVID-19 symptoms remaining the same or at least a single category improvement from baseline. | Up to 28 Days | 
| Time to Alleviation of COVID-19 Symptoms (21.5 Hours) | COVID-19 symptoms were evaluated using the first 12 items in the COVID-19 Symptom Diary, which included the following 12 items: nasal congestion or runny nose, sore throat, cough, shortness of breath, muscle or body aches, fatigue, headache, chills/sweats, feeling hot or feverish, nausea, vomiting, and diarrhea. The symptoms were scored on the 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe). Time to alleviation of COVID-19 symptoms is defined as the length of time taken from start of treatment to the point at which the following criterion is met and maintained for at least 21.5 hours: Score of 0 or 1 on Items 1-12 of the COVID-19 Symptom Diary, regardless of if the symptom is pre-existing or new. | Up to 28 Days | 
| Time to Alleviation of COVID-19 Symptoms (43 Hours) | COVID-19 symptoms were evaluated using the first 12 items in the COVID-19 Symptom Diary, which included the following 12 items: nasal congestion or runny nose, sore throat, cough, shortness of breath, muscle or body aches, fatigue, headache, chills/sweats, feeling hot or feverish, nausea, vomiting, and diarrhea. The symptoms were scored on the 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe). Time to alleviation of COVID-19 symptoms is defined as the length of time taken from start of treatment to the point at which the following criterion is met and maintained for at least 43 hours: Score of 0 or 1 on Items 1-12 of the COVID-19 Symptom Diary, regardless of if the symptom is pre-existing or new. | Up to 28 Days | 
| Duration of Fever | Duration of fever was defined as the time from start of treatment to return to an afebrile state (temperature ≤ 37.5°C) maintained for at least 21.5 hours. | Up to 28 Days | 
| Percentage of Participants With COVID-19 Related Complications | COVID-19 related complications include death, hospitalization, radiologically confirmed pneumonia, acute respiratory failure, sepsis, coagulopathy, pericarditis, myocarditis, and cardiac failure. | Up to 33 Days | 
| Time to Alleviation of an Individual Symptom | The COVID-19 Symptom Diary included the following 14 items: nasal congestion or runny nose, sore throat, cough, shortness of breath, muscle or body aches, fatigue, headache, chills/sweats, feeling hot or feverish, nausea, vomiting, diarrhea, sense of smell over the past 7 days and sense of taste over the past 7 days. The severity of items 1-12 was recorded on a 4-point Likert scale (none=0, mild=1, moderate=2, severe=3). Items 13-14 were recorded on a 3-point Likert scale (same as usual=0, less than usual=1, no sense=2). Time to alleviation of an individual symptom was defined as the time taken from the start of treatment to the point at which the following criterion was met and maintained (for each individual symptom) for at least 21.5 hours: score of 0 or 1 for Items 1-12 of the COVID-19 Symptom Diary; score of 0 for Items 13 and 14 of the COVID-19 Symptom Diary. | Up to 28 Days | 
| Percentage of Participants With Adverse Events (AEs) | An AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any of the following: any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition not present at baseline or related to a protocol-mandated intervention. | Up to 33 Days | 
| Plasma Concentrations of AT-511, AT-551, AT-229 and AT-273 for Participants Treated With 550 mg AT-527 | AT-511 is the free base form of AT-527. Its major metabolites are AT-551, AT-229, and AT-273. | Day 1: pre-dose, 1 hour, 3 hours; Day 3: pre-dose; Day 5: pre-dose, 3 hours, 48 hours | 
| Plasma Concentrations of AT-511, AT-551, AT-229 and AT-273 for Participants Treated With 1100 mg AT-527 | AT-511 is the free base form of AT-527. Its major metabolites are AT-551, AT-229, and AT-273. | Day 1: pre-dose, 1 hour, 4 hours; Day 3: pre-dose; Day 5: pre-dose, 1 hour, 4 hours, 48 hours |