A Pragmatic Randomized Trial to Evaluate the Effectiveness of High-Dose Quadrivalent Influenza Vaccine vs. Standard-Dose Quadrivalent Influenza Vaccine in Older Adults

The primary objective of this study is to evaluate the relative vaccine effectiveness of the **high-dose quadrivalent influenza vaccine (QIV-HD)** compared to the standard-dose quadrivalent influenza vaccine (QIV-SD) in reducing the risk of hospitalization for influenza or pneumonia, a composite endpoint, in older adults. This is clinically relevant as it addresses the prevention of severe outcomes associated with influenza and pneumonia, which are significant causes of morbidity and mortality in the elderly population.

Secondary objectives include evaluating the relative vaccine effectiveness of QIV-HD versus QIV-SD in reducing the risk of:

• Hospitalization for any cardio-respiratory disease, a composite endpoint, in older adults.
• All-cause hospitalization in older adults.
• All-cause mortality in older adults.
• Hospitalization specifically for influenza in older adults.
• Hospitalization for pneumonia in older adults.

The clinical trial focuses on the **prevention of influenza infection in older adults**. The study population includes both male and female participants aged 65 years and above, with the age range potentially adjusted according to the Danish government's recommendations for the influenza seasons of 2022/2023 and 2023/2024. The trial does not specifically target a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are selected based on their age, with no upper age limit unless specified by governmental guidelines. The trial does not impose specific lifestyle considerations such as diet or physical activity. The primary objective is to assess the relative vaccine effectiveness of QIV-HD versus QIV-SD in reducing the risk of hospitalization due to influenza or pneumonia in this demographic.

The clinical trial is designed to evaluate the effectiveness of a high-dose quadrivalent influenza vaccine compared to a standard-dose quadrivalent influenza vaccine in older adults. This study employs a **randomized**, **controlled** design, ensuring that participants are randomly assigned to receive either the high-dose or standard-dose vaccine, with neither the participants nor the investigators aware of the group assignments, thus maintaining a **double-blind** methodology. The trial is set to commence on October 1, 2022, with an estimated completion date of August 31, 2025, spanning approximately three years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (65 years and above, subject to modifications based on governmental recommendations). Following the initial visit, participants will receive the assigned vaccine via **intramuscular injection**. Subsequent follow-up visits will be scheduled to monitor the participants' health status and collect data on any hospitalizations due to influenza or pneumonia, which constitute the primary endpoint. Secondary endpoints include hospitalization for any cardio-respiratory disease, all-cause hospitalization, all-cause mortality, and specific hospitalizations for influenza or pneumonia.

The expected duration of participant involvement is up to one year, with conditions for early termination including withdrawal of consent or any adverse events that may compromise participant safety. Data collection will primarily utilize Danish nationwide administrative health registries and medical record reviews, minimizing the need for additional diagnostic or monitoring procedures. The trial is categorized as low-intervention, as the vaccines are already approved and used according to their marketing authorization, with no additional risks posed to participants beyond standard vaccination protocols.

The clinical trial involves the administration of a **COVID-19, RNA-BASED VACCINE** containing the active substances **ELASOMERAN** and **IMELASOMERAN**. This vaccine is formulated as a pharmaceutical form identified as PHF539 and is administered via **intramuscular injection**. The dosage is set at 50 µg microgram(s) per administration, with a maximum total dose of 50 µg microgram(s) over a treatment period of one day. The active substances, **ELASOMERAN** and **IMELASOMERAN**, are nucleic acids, with **ELASOMERAN** also known as mRNA-1273, encoding the viral spike protein of SARS-CoV-2, and **IMELASOMERAN** encoding the spike protein of the SARS-CoV-2 variant B.1.1.529.

The trial also includes the use of **Efluelda**, a suspension for injection, which serves as a comparator treatment. This vaccine contains inactivated influenza virus strains, including **B/PHUKET/3073/2013-LIKE VIRUS**, **B/WASHINGTON/02/2019 - LIKE VIRUS**, **A/VICTORIA/2570/2019 (H1N1)PDM09-LIKE STRAIN**, and **INFLUENZA A VIRUS, A/CAMBODIA/E0826360/2020 (H3N2) - LIKE STRAIN**. The vaccine is administered intramuscularly with a maximum daily and total dose of 240 µg microgram(s) over a one-day treatment period.

Additionally, **Vaxigriptetra** is used as an auxiliary treatment in the study. This vaccine is also a suspension for injection and contains similar inactivated influenza virus strains as **Efluelda**. It is administered intramuscularly with a maximum daily and total dose of 60 µg microgram(s) over a one-day treatment period.

Lastly, **Influvactetra** is another auxiliary treatment used in the trial. It is a suspension for injection containing inactivated influenza virus strains, including **B/PHUKET/3073/2013-LIKE VIRUS**, **B/WASHINGTON/02/2019 - LIKE VIRUS**, **A/VICTORIA/2570/2019 (H1N1)PDM09-LIKE STRAIN**, and **A/CAMBODIA/E0826360/2020 (H3N2)-LIKE STRAIN**. This vaccine is administered intramuscularly with a maximum daily and total dose of 60 µg microgram(s) over a one-day treatment period.

The efficacy of the clinical trial will be assessed by evaluating the relative vaccine effectiveness of the high-dose quadrivalent influenza vaccine (QIV-HD) compared to the standard-dose quadrivalent influenza vaccine (QIV-SD) in reducing the risk of hospitalization for influenza or pneumonia in older adults. The primary endpoint for efficacy assessment is the rate of hospitalization due to influenza or pneumonia, which serves as a composite endpoint. Secondary endpoints include hospitalization for any cardio-respiratory disease, all-cause hospitalization, all-cause mortality, hospitalization for influenza, and hospitalization for pneumonia.

Data collection for efficacy assessment will be conducted through the Danish nationwide administrative health registries and medical record review. This approach ensures comprehensive and accurate data collection without additional diagnostic or monitoring procedures that could pose risks to participants. The trial is designed as a pragmatic randomized trial, and the data will be analyzed to determine the relative effectiveness of the vaccines in achieving the specified endpoints. The study is expected to conclude by August 31, 2025, with recruitment having started on October 1, 2022.