Evaluation of Bemnifosbuvir Hemisulfate Efficacy and Safety in High-Risk COVID-19 Outpatients: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2023-504540-33-00
- Protocol
- AT-03A-017
- Sponsor
- Atea Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of Bemnifosbuvir (BEM) compared with placebo in reducing all-cause hospitalization or all-cause death in outpatients with COVID-19 who are receiving only supportive care. This is clinically relevant as it aims to determine the potential of BEM to decrease severe outcomes in high-risk patients, thereby potentially reducing healthcare burden and improving patient prognosis.
Secondary objectives include:
- Evaluating the efficacy of BEM compared with placebo on COVID-19-related hospitalization or all-cause death through Day 29, all-cause death through Day 29 and Day 60, and COVID-19-related complications such as radiologically confirmed pneumonia, acute respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, and cardiac failure through Day 29.
- Assessing COVID-19-related medically attended visits, including hospitalization, emergency room visits, urgent care visits, physician's office visits, or telemedicine visits, or all-cause death through Day 29 and Day 60, as well as COVID-19 symptom relapse.
- Evaluating the antiviral activity of BEM compared with placebo on viral load rebound.
- Assessing the safety of BEM compared with placebo.
Participants
The clinical trial involves a total of **2116 participants** diagnosed with **COVID-19**. The study population includes both male and female subjects, encompassing a wide age range from adolescents aged 12 years to adults over 70 years. Participants were selected based on their positive SARS-CoV-2 diagnostic test and categorized as having mild to moderate COVID-19 symptoms. The trial specifically targets individuals at high risk of severe outcomes, including those aged 70 years and older, or younger individuals with comorbidities such as obesity, diabetes mellitus, cardiovascular disease, or chronic lung disease. Additionally, individuals with conditions like Down syndrome, sickle cell disease, dementia, or those undergoing immunosuppressive treatments are included. The trial also considers lifestyle factors such as the ability to take oral medications and compliance with study requirements. Vulnerable populations, including adolescents and those with specific immunocompromising conditions, are part of the study, ensuring a comprehensive evaluation of the treatment's efficacy across diverse risk groups.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **Bemnifosbuvir Hemisulfate** in high-risk outpatients with **COVID-19**. The primary objective is to assess the reduction in all-cause hospitalization or death in participants receiving only supportive care. The trial is expected to run until June 30, 2024, with recruitment having commenced on March 8, 2023. Participants will be randomly assigned to receive either Bemnifosbuvir Hemisulfate, a placebo, or Paxlovid, with the treatment administered orally in the form of tablets.
The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a positive SARS-CoV-2 test and the presence of mild to moderate COVID-19 symptoms. Participants must also meet specific risk factors related to age and underlying health conditions. Following the screening, participants will undergo randomization and commence the treatment phase, which lasts for a maximum of five days. Follow-up visits are scheduled to monitor the participants' health status and collect data on primary and secondary endpoints, including hospitalization rates, mortality, and adverse events. The end-of-study visit will occur on Day 29, with additional follow-up extending to Day 60 for certain secondary endpoints.
Participant involvement is expected to last approximately two months, from the initial screening to the final follow-up. Conditions that may lead to early termination from the study include the development of severe adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial's design ensures that all participants, investigators, and study personnel remain blinded to the treatment assignments to maintain the integrity of the data collected.
Treatment
The clinical trial involves the administration of **Paxlovid**, a combination of **nirmatrelvir** and ritonavir, formulated as film-coated tablets. Each tablet contains 150 mg of nirmatrelvir and 100 mg of ritonavir. The medication is administered orally, with a maximum daily dose of 600 mg, and a total maximum dose of 3000 mg over a treatment period of 5 days. The pharmaceutical form is designed to ensure optimal absorption and efficacy. The trial monitors participant compliance through regular assessments and adherence checks.
Another experimental treatment in the trial is **Bemnifosbuvir Hemisulfate**, also known by its sponsor product code AT-527. This antiviral agent is provided in tablet form and is administered orally. The maximum daily dose is 1100 mg, with a total maximum dose of 5500 mg over a 5-day treatment period. The chemical nature of the active substance is designed to target viral replication, and participant adherence is monitored through scheduled dosing and follow-up visits.
The study also includes a **placebo** group to match Bemnifosbuvir Hemisulfate, ensuring the double-blind nature of the trial. The placebo is designed to mimic the appearance and administration route of the active treatment, maintaining the integrity of the study's blinding process. Participants receiving the placebo follow the same dosing schedule as those receiving the active treatment, with compliance monitored similarly.
Efficacy
The efficacy of Bemnifosbuvir in high-risk outpatients with COVID-19 will be assessed through a Phase 3 randomized, double-blind, placebo-controlled study. The primary efficacy endpoint is the proportion of subjects in the supportive-care-only population who are hospitalized for any cause or die due to any cause through Day 29. Secondary endpoints include the proportion of subjects with COVID-19-related hospitalization or death through Day 29, the proportion of subjects who die due to any cause through Day 29 and Day 60, and the proportion of subjects with COVID-19-related complications such as radiologically confirmed pneumonia, acute respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, and cardiac failure through Day 29.
Additional secondary endpoints involve the proportion of subjects with COVID-19-related medically attended visits, symptom relapse, and viral load rebound through Day 29. The incidence and severity of adverse events (AEs) and serious adverse events (SAEs) will also be monitored. Efficacy parameters will be collected and analyzed at specified timepoints, including Day 29 and Day 60, to evaluate the impact of Bemnifosbuvir compared to placebo in reducing all-cause hospitalization or death in the study population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Willing and able to provide informed consent.
- 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.
- 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 -No clinical signs indicative of severe or critical illness severity
- 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.
- Females of childbearing potential must have a negative pregnancy test prior to initiation of study drug.
- Subject must be able to take oral tablet medications.
- Subject is, in the opinion of the investigator, willing and able to comply with the study drug regimen and all other study requirements.
- Subject must be high risk, defined below. • Age ≥70 years OR • Age ≥55 years with one of the following risk factors: -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 50 to 54 inclusive with two of the following risk factors: -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, -Care home residents -One of the following immunocompromising conditions or immunosuppressive treatments: --On immunosuppressive regimens including chemotherapy for the treatment of cancer --Hematologic malignancy associated with poor response to COVID-19 vaccines (e.g., CLL, non-Hodgkin lymphoma, multiple myeloma, acute leukemia) --Being within 2 years of a hematopoietic stem cell transplant --Receipt of a solid-organ transplant and on immunosuppressive therapy --Human immunodeficiency virus (HIV) infection (untreated) or with CD4+ T lymphocyte count <350 cells per cubic millimeter (mm3) --Moderate or severe primary immunodeficiency disorder --Active treatment with an immunosuppressive medication regimen (e.g., high-dose corticosteroids [ie, 20 mg of prednisone daily or equivalent for ≥2 weeks], alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents that are severely immunosuppressive, anti-tumor necrosis factor (TNF) blockers, biologics that are immunosuppressive) • Enrollment of high-risk adolescents (≥ 12 years to 17 years) will be allowed after the planned, pre-specified interim analysis for which 65% of the supportive-care-only stratum completed the follow-up period (Day 29). A DSMB recommendation that the study continue at this interim analysis point will trigger enrollment of adolescents.
Exclusion Criteria
- Female subject is pregnant or breastfeeding.
- 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, 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).
- Admitted to a hospital within 90 days prior to randomization due to COVID-19 or is hospitalized (inpatient) for any reason at randomization. Note: If local policy requires COVID-19 isolation or internment in a hospital or similar facility, but subjects otherwise meet inclusion criteria, this exclusion may not apply. However, subjects under clinical observation at a clinic/study site or hospital with plans to remain in that setting overnight are not study eligible.
- In the opinion of the investigator, is likely to experience imminent deterioration and require hospitalization within 24 hours.
- 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.
- Initiation or planned initiation of remdesivir for treatment of the current SARS-CoV-2 infection.
- 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 nirmatrelvir/ritonavir, molnupiravir, favipiravir, mAbs) will be permitted
- 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) or 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.
- Receiving dialysis or have severe renal impairment [i.e. estimated glomerular filtration rate (eGFR) <30 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 <30 mL/min/1.73 m2, a confirmatory test should be performed at screening to confirm eligibility before the first dose of study drug.
- History of severe hepatic impairment (Child-Pugh Class C)
- Known allergy or hypersensitivity to components of study drug.
- Malabsorption syndrome or other condition that would interfere with enteral absorption.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 08 Mar 2023 | 30 |
 Latvia | Not Recruiting | 08 Mar 2023 | 30 |
 The Netherlands | Not Recruiting | 08 Mar 2023 | — |
 Romania | Not Recruiting | 08 Mar 2023 | 100 |
 Spain | Not Recruiting | 08 Mar 2023 | 24 |
 Sweden | Not Recruiting | 08 Mar 2023 | 30 |
| Netherlands | — | — | 140 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Paxlovid 150 mg + 100 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL | 600 | 5 | PRD9472287 |
Paxlovid 150 mg + 100 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL | 200 | 5 | PRD9472501 |
Placebo to match Bemnifosbuvir Hemisulfate | Placebo | N/A | — | — | — | N/A |
Bemnifosbuvir Hemisulfate | Test | TABLET | ORAL | 1100 | 5 | PRD10369192 |