A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Bemnifosbuvir in High-Risk Outpatients with COVID-19

1. Willing and able to provide informed consent.
2. Positive SARS-CoV-2 diagnostic test (RT-PCR or validated rapid antigen test)
conducted <= 5 days prior to randomization. Note: The test may be obtained
locally. A documented historical record of positive result (RT-PCR or validated
rapid antigen test) from test conducted <= 5 days prior to randomization is
acceptable.
3. Mild or moderate COVID-19 with symptom onset <= 5 days before randomization
and at least one COVID-19 related symptom present at time of screening:
• Mild COVID-19:
- Symptoms of mild illness with COVID-19, which could include fever,
cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea,
and loss of taste or smell, without shortness of breath or dyspnea
- No clinical signs indicative of moderate, severe, or critical illness
severity
• Moderate COVID-19:
- Symptoms of moderate illness with COVID-19, which could include any
symptom of mild illness or shortness of breath with exertion
- Clinical signs suggestive of moderate illness with COVID-19, such as
respiratory rate >= 20 breaths per minute, heart rate >= 90 beats per minute;
with saturation of oxygen (SpO2) > 93% on room air at sea level
- No clinical signs indicative of severe or critical illness severity
4. For females of childbearing potential: agreement to remain abstinent
(refrain from heterosexual intercourse) or use adequate contraception during
the treatment period and for 30 days after the final dose of study drug.
5. Females of childbearing potential must have a negative pregnancy test prior
to initiation of study drug.
6. Subject must be able to take oral tablet medications.
7. Subject is, in the opinion of the investigator, willing and able to comply
with the study drug regimen and all other study requirements.
8. Subject must be high risk, defined below.
• Age >=80 years OR
• Age >=65 years with one of the following:
- Obesity (body mass index [BMI] >=30 kg/m2)
- Diabetes mellitus
- Cardiovascular disease (including congenital heart disease) or
hypertension (with at least one medication recommended or prescribed)
- Chronic lung disease requiring routine therapy (e.g., chronic
obstructive pulmonary disease [COPD], moderate-to-severe asthma, interstitial
lung disease, cystic fibrosis, pulmonary hypertension)
OR
• Age >=18 years with one of the following:
- Down syndrome, sickle cell disease, dementia, Parkinson*s disease, or
care home residents
- One of the following immunocompromising conditions or immunosuppressive
treatment:
o Receiving chemotherapy or other therapies for cancer
o Hematologic malignancy (active or in remission)
o Being within 2 years from receiving a hematopoietic stem cell or at
any time following a solid organ transplant
o Human immunodeficiency virus (HIV) infection untreated or with CD4+ T
lymphocyte count <350 cells per cubic millimeter (mm3) within the past 6
months
o Combined primary immunodeficiency disorder
o Taking immunosuppressive medications (e.g., drugs to suppress
rejection of transplanted organs or to treat rheumatologic and gastrointestinal
conditions such as anti-tumor necrosis factor (TNF) agents, mycophenolate, or
rituximab)

1. Female subject is pregnant or breastfeeding.
2. Clinical signs or symptoms indicative of severe or critical COVID-19
illness, including any of the following: shortness of breath at rest,
respiratory rate >=*30 breaths per minute, heart rate >= 125 beats per minute,
SpO2 <= 93% on room air at sea level, partial pressure of oxygen/ fraction of
inspired oxygen (PaO2/FiO2) <300, shock (defined by systolic blood pressure
< 90 mm Hg or diastolic blood pressure < 60 mm Hg or requiring
vasopressors), multi-organ dysfunction/failure, respiratory distress,
respiratory failure; requirement of endotracheal intubation, mechanical
ventilation, oxygen delivered by high-flow nasal cannula, noninvasive positive
pressure ventilation, extracorporeal membrane oxygenation (ECMO).
3. Admitted to a hospital within 90 days prior to randomization due to COVID-19
or is hospitalized (inpatient) at randomization due to COVID-19. Note: If
local policy requires COVID-19 isolation or internment in a hospital or similar
facility, but subjects otherwise meet criteria, this exclusion may not apply.
4. In the opinion of the investigator, is likely to experience imminent
deterioration and require hospitalization within 24 hours.
5. Use of other investigational drugs within 30 days prior to planned dosing,
or plans to enroll in another clinical trial of an investigational agent while
participating in the present study, except for unblinded protocols that don*t
include direct acting antivirals for COVID-19 (e.g., open-label oncological
regimen variations or biologic studies). Note: Prior to enrolling subjects
that are on other open-label studies, it is the site*s responsibility to ensure
that the study criteria for that study allow for enrollment into this study.
6. Initiation or planned initiation of remdesivir for treatment of the current
SARS-CoV-2 infection.
7. Requirement of any prohibited medications, as described in Section 5.7 of
protocol, including either hydroxychloroquine or amiodarone within 3 months
prior to screening. Note: Subjects who had already initiated any COVID-19 drug
with antiviral effects intended to treat symptomatic SARS-CoV-2 infection (>= 24
hours prior to randomization) will be excluded. During screening (or within 24
hours prior to or after randomization), locally available COVID-19 drugs with
antiviral effects (including but not limited to Paxlovid, molnupiravir,
favipiravir, mAbs) will be permitted, as long as there are no concerns for DDIs
(e.g., remdesivir would not be permitted).
8. Other known active viral or bacterial infection at the time of screening,
such as influenza (i.e., as verified by a locally available rapid flu test at
screening_ and respiratory syncytial virus (RSV). Note: This exclusion does
not apply to subjects with stable chronic viral infections, such as chronic HCV
or HIV providing other eligibility criteria are met.
9. Receiving dialysis or have known moderate to severe renal impairment [i.e.
estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 within 6
months of the screening visit, using the serum creatinine-based CKD-EPI
formula]. Note: If the investigator suspects the subject may have eGFR <45
mL/min/1.73 m2, a confirmatory test should be performed at screening to confirm
eligibility before the first dose of study drug.
10. History of severe hepatic impairment (Child-Pugh Class C)
11. Known allergy or hypersensitivity to components of study drug.
12. Malabsorption syndrome or other condition that would interfere with enteral
absorption.
13. Any clinically significant medical condition or known laboratory
abnormality that, in the opinion of the investigator, could jeopardize the
safety of the subject or impact subject compliance or safety/efficacy
observations in the study.