Operational Framework and Feasibility of the GALFLU Study: A Pragmatic Individually Randomized Controlled Trial Evaluating High-Dose Versus Standard-Dose Influenza Vaccination in Older Adults

Background: Optimizing influenza vaccination strategies for older adults remains a public health priority. Whilst the high-dose inactivated influenza vaccine (HDIIV) has demonstrated superior immunogenicity and efficacy compared to standard-dose inactivated influenza vaccines (SDIIV), the real world effectiveness against severe outcomes has mostly relied on observational data and small RCTs, so is yet to be explored within large-scale individually randomised trials, particularly within publicly funded health systems. Methods: GALFLU is a pragmatic, individually randomized, open-label clinical trial evaluating the effectiveness of HDIIV versus SDIIV in adults aged 65 to 79 years in Galicia, Spain, during the 2023/2024 and 2024/2025 influenza seasons. The study integrated the methodological rigor and efficiency of individual randomization into existing public health infrastructure, and real-time, population-based digital health registries enabled large-scale data capture at low cost and with minimal burden to participants, under real-world conditions. The main endpoint is relative vaccine effectiveness (rVE) against a composite of influenza or pneumonia-related hospitalizations. Secondary endpoints involve rVE against hospitalization for any cardio-respiratory disease (composite); hospitalization with laboratory-confirmed influenza; all-cause hospitalization; all-cause mortality; hospitalization for influenza; and hospitalization for pneumonia. Exploratory endpoints include exacerbation of existing conditions and impact on healthcare resource utilisation. Results: GALFLU demonstrates the feasibility of embedding large-scale, pragmatic randomized controlled trials (RCTs) within routine clinical practice in Galicia, Spain. The design enabled large and efficient recruitment. Total 133,822 participants were randomized, 59,490 in 2023/24 season and 74,986mar in 2024/25 season, all within 4 weeks for 2023/-24 season, and 5 weeks for 2024/25 season. Follow-up was completed for over 99% of the participants through automated linkage to clinical and laboratory registries. Conclusions: GALFLU provides a scalable, low-burden model for generating robust real-world evidence from RCTs embedded within public health programs. This operational framework serves as a blueprint for future comparative vaccine evaluations and supports regulatory and policy decisions with high-quality, population-level data. GALFLU exemplifies how public health systems can evolve into learning health systems by integrating pragmatic trials into routine care. Trial registration: EU Clinical Trials Register (EU CT number: 2023-506977-36-00); ClinicalTrials.gov Identifier: NCT06141655 .