A Phase 3, Multicenter, Randomized, Partially Blinded, Palivizumab-Controlled Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of MK-1654 in Infants and Children at Increased Risk for Severe RSV Disease

The primary objective of this study is to evaluate the **safety** and tolerability of clesrovimab (MK-1654) compared to palivizumab in infants and children at increased risk for severe **respiratory syncytial virus (RSV)** disease during RSV Season 1. This is assessed by the proportion of participants experiencing adverse events (AEs). The clinical relevance of this objective lies in determining the potential of clesrovimab as a safer alternative to palivizumab, which is crucial for the prevention of RSV infection in a vulnerable pediatric population.

Secondary objectives include:

• Estimating the efficacy of clesrovimab compared to palivizumab by assessing the incidence of RSV-associated medically attended lower respiratory infection (MALRI) from Days 1 through 150 post Dose 1 in RSV Season 1.
• Estimating the incidence of RSV-associated hospitalizations from Days 1 through 150 post Dose 1 in RSV Season 1 in both the clesrovimab and palivizumab groups.
• Describing the serum pharmacokinetic (PK) concentration of clesrovimab at Days 7, 150, and 240 after the dose in RSV Season 1.
• Describing the safety of clesrovimab administered in RSV Season 2, as assessed by the proportion of participants experiencing AEs.
• Describing the serum PK concentration of clesrovimab at Days 7 and 150 postdose in RSV Season 2.

The clinical trial involves a total of **619 participants** who are infants and children at increased risk for severe **respiratory syncytial virus (RSV)** disease. The study population includes both male and female subjects with a chronological age ranging from birth up to 1 year, specifically those entering their first RSV season. Participants were selected based on their increased risk for severe RSV infection, as recommended to receive palivizumab according to national or local guidelines or professional society recommendations. The trial population is characterized as a vulnerable group due to their young age and heightened risk factors. No specific lifestyle considerations such as diet or physical activity are highlighted for this study. The selection criteria ensure that participants are available to complete the follow-up period, emphasizing the importance of monitoring safety and tolerability during the trial.

The clinical trial is designed to evaluate the **safety** and efficacy of **Clesrovimab** (MK-1654) compared to **Palivizumab** in infants and children at increased risk for severe **Respiratory Syncytial Virus (RSV)** disease. This is a Phase 3, multicenter, randomized, partially blinded, and **Palivizumab**-controlled study. The trial is expected to run from November 30, 2021, to April 27, 2026. Participants will be randomly assigned to receive either **Clesrovimab**, **Palivizumab**, or a placebo, with the primary objective being the assessment of adverse events (AEs) during the first RSV season.

The study will include several visits, starting with a screening visit to determine eligibility based on criteria such as age (from birth up to 1 year) and increased risk for severe RSV infection. Participants must be available to complete the follow-up period. The trial will involve multiple follow-up visits to monitor the occurrence of solicited injection-site AEs, systemic AEs, and other specific AEs of interest, such as anaphylaxis and rash. The end-of-study visit will conclude the participant's involvement, assessing the overall safety and efficacy outcomes.

Participant involvement is expected to last through two RSV seasons, with the first season focusing on primary endpoints such as the percentage of participants experiencing solicited AEs and serious AEs (SAEs). Secondary endpoints will include the percentage of participants with RSV-associated medically attended lower respiratory infections and hospitalizations. The trial will also measure the serum concentration of **Clesrovimab** post-dose in both RSV seasons.

Conditions that may lead to early termination from the study include the occurrence of severe adverse reactions or the participant's inability to comply with the study protocol. The trial is not classified as a low-intervention study, and it aims to confirm the safety and efficacy of **Clesrovimab** in the target population for prophylaxis against severe RSV disease.

The clinical trial involves the administration of **Clesrovimab**, an experimental medication, which is a **solution for injection**. The active substance, clesrovimab, is a protein of non-human origin. The pharmaceutical form is a solution for injection, and it is administered via the **intramuscular** route. The maximum daily dose is 210 mg, with a total maximum dose of 315 mg over a treatment period of 60 days. The medication is provided by Merck & Co. Inc. and is identified by the sponsor product code MK-1654.

In addition to the experimental treatment, the study includes a comparator treatment, **Synagis** (palivizumab), which is also a solution for injection. Palivizumab is a protein-based medication, administered intramuscularly. The dosing regimen for Synagis is 15 mg/kg, with a maximum total dose of 75 mg/kg over a 120-day treatment period. This comparator is provided by AstraZeneca AB and is used to evaluate the efficacy and safety of the experimental treatment.

The study also utilizes a **placebo** control, specifically a saline solution for injection, referred to as "Placebo to MK-1654 - Saline for injection." This placebo is used to maintain the study's partially blinded design. The placebo is administered intramuscularly, mirroring the administration route of the active treatments, although specific dosing details are not applicable.

Additionally, **Isotone Natriumchloridlösung 0,9 % Braun Injektionslösung** is used as a non-experimental treatment. This solution for injection contains **sodium chloride** as the active substance and is classified as a chemical compound. It is provided by B. Braun Melsungen AG and serves as a solvent or diluting agent in the study. The administration route is intramuscular, consistent with the other treatments in the trial.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the safety and tolerability of **Clesrovimab** (MK-1654) compared to palivizumab in infants and children at increased risk for severe respiratory syncytial virus (RSV) disease. These endpoints include the percentage of participants experiencing solicited injection-site adverse events (AEs), daily body temperature with fever, systemic AEs, anaphylaxis/hypersensitivity AEs of special interest (AESI), rash AESI, non-serious AEs, and serious AEs (SAEs) during RSV Season 1.

Secondary endpoints will further evaluate the efficacy by measuring the percentage of participants with RSV-associated medically attended lower respiratory infection (MALRI) and RSV-associated hospitalization in RSV Season 1. Additionally, the trial will assess the percentage of participants with solicited injection-site AEs, daily body temperature with fever, systemic AEs, anaphylaxis/hypersensitivity AESI, rash AESI, non-serious AEs, and SAEs through 180 days postdose in RSV Season 2. The serum concentration of **Clesrovimab** after dosing in both RSV Season 1 and Season 2 will also be measured to evaluate pharmacokinetics.