Efficacy and Safety Evaluation of Molnupiravir in Non-Hospitalized Adults with SARS-CoV-2 Infection at High Risk for Disease Progression

The primary objective of this study is to evaluate the **efficacy** of molnupiravir (MOV) compared with placebo in non-hospitalized adults with COVID-19 who are at high risk for disease progression. This is assessed by the percentage of participants in the modified intent-to-treat (mITT) population who experience one or more of the following outcomes from randomization through Day 29: hospitalization (all-cause), death (all-cause), or a COVID-19-related medically attended visit (MAV). Additionally, the study aims to evaluate the safety and tolerability of MOV compared with placebo in the all-participants-as-treated (APaT) population. These objectives are clinically relevant as they address the potential of MOV to reduce severe outcomes in high-risk COVID-19 patients, which is critical for managing healthcare resources and improving patient outcomes.

Secondary objectives include:

• Evaluating the efficacy of MOV compared with placebo by the time to sustained alleviation of all 8 selected self-reported COVID-19 signs/symptoms from randomization through Day 29.
• Assessing the antiviral activity of MOV compared with placebo by the change from baseline in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA) titer and the percentage of participants with undetectable SARS-CoV-2 RNA in nasopharyngeal swabs at various time points.
• Evaluating the efficacy of MOV compared with placebo by the percentage of participants in the mITT population who experience hospitalization (all-cause) or death (all-cause) from randomization through Day 29.
• Assessing the efficacy of MOV compared with placebo by the percentage of participants with clinically important medical interventions associated with a COVID-19-related MAV and/or hospitalization from randomization through Day 29.
• Evaluating the efficacy of MOV compared with placebo by the time to sustained alleviation of all 15 self-reported COVID-19 signs/symptoms without relapse from randomization through Day 29 in the mITT population.
• Assessing the efficacy of MOV compared with placebo by the time to sustained resolution without relapse of all 8 selected self-reported COVID-19 signs/symptoms from randomization through Day 29 in the mITT population.

The clinical trial investigating the efficacy and safety of molnupiravir (MOV) in comparison to placebo for **SARS-CoV-2 (COVID-19) infection** includes a total of 2,329 participants. The study population comprises individuals of any gender, aged over 18 years, who have documented SARS-CoV-2 infection with sample collection less than four days prior to randomization. Participants must have experienced the initial onset of COVID-19 symptoms within four days before randomization and exhibit more than two specific symptoms on the day of randomization. The trial includes individuals with characteristics or medical conditions associated with a high risk of severe illness from COVID-19, such as advanced age over 75 years, immunocompromised status, or neurocognitive or physical disabilities. Participants unable to receive treatment with nirmatrelvir/ritonavir due to various medical or logistical reasons are also included. Both male and female subjects are part of the study, and the trial does not specifically target a vulnerable population. The selection process ensures a diverse representation of individuals at risk of severe COVID-19 outcomes, without specific lifestyle considerations such as diet or physical activity being highlighted.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy and safety of **molnupiravir** in non-hospitalized adults with **COVID-19** who are at high risk for disease progression. The trial aims to assess the percentage of participants experiencing hospitalization, all-cause mortality, or a COVID-19 related medically attended visit from randomization through Day 29. The study will also evaluate the safety and tolerability of molnupiravir compared to placebo. The trial is expected to commence recruitment on February 15, 2025, and conclude by April 22, 2031.

Participants will be involved in the study for a maximum of 29 days, with the treatment period lasting up to 5 days. The study will include several key visits: an initial screening visit to confirm eligibility, randomization, and baseline assessments. Follow-up visits will occur throughout the study to monitor the participants' health status, collect data on any adverse events, and assess the primary and secondary endpoints. The end-of-study visit will finalize data collection and ensure participant safety post-treatment.

Inclusion criteria require participants to be over 18 years of age, with documented **SARS-CoV-2** infection and initial onset of symptoms within four days prior to randomization. Participants must also have characteristics or medical conditions associated with a high risk of severe illness from COVID-19. Exclusion criteria are not explicitly detailed in the provided data. Participants may be terminated early from the study if they experience significant adverse events or if they withdraw consent. The study will utilize oral administration of molnupiravir or matching placebo tablets, with a maximum daily dose of 1600 mg and a total dose not exceeding 8000 mg over the treatment period.

The clinical trial involves the administration of **molnupiravir**, an experimental antiviral medication, in the form of a **tablet**. The active substance, molnupiravir, is chemically synthesized and is identified by the sponsor product code MK-4482. The pharmaceutical form is a tablet, and the medication is administered **orally**. The dosing regimen for molnupiravir involves a maximum daily dose of 1600 mg, with a total maximum dose of 8000 mg over a treatment period of up to 5 days. The trial aims to evaluate the efficacy and safety of molnupiravir in non-hospitalized adults with COVID-19 who are at high risk for disease progression.

In addition to the experimental treatment, the study includes the use of **Molnupiravir Matching placebo tablets** as a comparator. These placebo tablets are designed to match the appearance of the molnupiravir tablets but do not contain the active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as the active treatment, following the same dosing schedule to ensure consistency across the study arms.

The efficacy of **molnupiravir** in the clinical trial will be assessed by evaluating the percentage of participants in the modified intent-to-treat (mITT) population who experience one or more of the following outcomes from randomization through Day 29: hospitalization (all cause), death (all cause), or a COVID-19 related medically attended visit (MAV). The primary endpoints include the percentage of participants who experienced one or more of these outcomes, as well as the percentage of participants who experienced an adverse event (AE) and those who discontinued the study intervention due to an AE.

Secondary endpoints will further assess efficacy by measuring the time to sustained alleviation without relapse of selected COVID-19 related signs and symptoms through Day 29, changes from baseline in SARS-CoV-2 viral load, and the percentage of participants with undetectable SARS-CoV-2 viral load. Additionally, the trial will evaluate the percentage of participants who experienced all-cause hospitalization or mortality, and those with clinically important medical interventions associated with COVID-19 related MAV or hospitalization through Day 29. The time to sustained resolution without relapse of selected COVID-19 related signs and symptoms will also be measured.