Pooled Analysis of Methodologically Harmonized Pragmatic Randomized Trials of High-Dose vs. Standard-Dose Influenza Vaccine Against Severe Clinical Outcomes (FLUNITY-HD)

This prespecified analysis will pool the datasets from two pragmatic randomized trials evaluating the relative vaccine effectiveness of high-dose vs. standard-dose influenza vaccine against severe clinical outcomes: the DANFLU-2 (A Pragmatic Randomized Trial to Evaluate the Effectiveness of High-Dose Quadrivalent Influenza Vaccine vs. Standard-Dose Quadrivalent Influenza Vaccine in Older Adults) trial and the GALFLU (Pragmatic Randomized Trial to Evaluate the Effectiveness of High-Dose Quadrivalent Influenza Vaccine vs. Standard-Dose Quadrivalent Influenza Vaccine in Adults Aged 65 to 79 Years in Galicia, Spain) trial. The purpose of the pooled analysis is to ensure adequate statistical power for evaluating relative vaccine effectiveness against severe clinical outcomes and to increase generalizability of the results by combining data from two countries.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Biological: High-Dose Influenza Vaccine; Biological: Standard-Dose Influenza Vaccine

• Study Type: Interventional
• Enrollment (Actual): 466320
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Capital Region
    • Hellerup, Capital Region, Denmark, 2900
      • Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pragmatic trials conducted to estimate the relative vaccine effectiveness of high-dose influenza vaccine compared with standard-dose influenza vaccine using the DANFLU-2 protocol or a protocol developed based on the DANFLU-2 protocol

Exclusion Criteria:

• Low data quality
• Influenza circulation threshold was not met in any of the study seasons
• Severe under-enrollment in all seasons

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-Dose Influenza Vaccine; Single injection of high-dose influenza vaccine at Day 0	Biological: High-Dose Influenza Vaccine; For this arm, the high-dose quadrivalent influenza vaccine Efluelda®/Fluzone® High-Dose Quadrivalent will be used.
Active Comparator: Standard-Dose Influenza Vaccine; Single injection of standard-dose influenza vaccine at Day 0	Biological: Standard-Dose Influenza Vaccine; Any standard-dose quadrivalent influenza vaccine administered in the governmental influenza vaccine programs may be used.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Hospitalization for influenza or pneumonia	≥14 days after vaccination up to 8 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Hospitalization for any cardio-respiratory disease	≥14 days after vaccination up to 8 months
All-cause hospitalization	≥14 days after vaccination up to 8 months
All-cause mortality	≥14 days after vaccination up to 8 months
Hospitalization for influenza	≥14 days after vaccination up to 8 months
Hospitalization for pneumonia	≥14 days after vaccination up to 8 months
Laboratory-confirmed influenza hospitalization	≥14 days after vaccination up to 8 months

Other Outcome Measures

Outcome Measure	Time Frame
Hospitalization for influenza or pneumonia (alternate definition)	≥14 days after vaccination up to 8 months
Hospitalization for pneumonia (alternate definition)	≥14 days after vaccination up to 8 months
Hospitalization for influenza (alternate definition)	≥14 days after vaccination up to 8 months
Hospitalization for any respiratory disease	≥14 days after vaccination up to 8 months
Hospitalization for any cardiovascular disease	≥14 days after vaccination up to 8 months
Hospitalization for myocardial infarction	≥14 days after vaccination up to 8 months
Hospitalization for heart failure	≥14 days after vaccination up to 8 months
Hospitalization for atrial fibrillation	≥14 days after vaccination up to 8 months
Hospitalization for stroke	≥14 days after vaccination up to 8 months
Major adverse cardiovascular events (MACE) defined as a composite of hospitalization for acute myocardial infarction, hospitalization for stroke, and cardiovascular death	≥14 days after vaccination up to 8 months
MACE defined as a composite of hospitalization for acute myocardial infarction, hospitalization for stroke, hospitalization for heart failure, and cardiovascular death (alternate definition #1)	≥14 days after vaccination up to 8 months
MACE defined as a composite of hospitalization for acute myocardial infarction, hospitalization for stroke, and all-cause death (alternate definition #2)	≥14 days after vaccination up to 8 months
Hospitalization requiring mechanical ventilation	≥14 days after vaccination up to 8 months
Laboratory-confirmed influenza	≥14 days after vaccination up to 8 months
Laboratory-confirmed pneumococcal pneumonia	≥14 days after vaccination up to 8 months
Laboratory-confirmed COVID-19	≥14 days after vaccination up to 8 months
Cardio-respiratory mortality	≥14 days after vaccination up to 8 months
Respiratory mortality	≥14 days after vaccination up to 8 months
Cardiovascular mortality	≥14 days after vaccination up to 8 months
In-hospital mortality	≥14 days after vaccination up to 8 months
Intensive care unit admission	≥14 days after vaccination up to 8 months
Any hospital contact associated with laboratory-confirmed influenza	≥14 days after vaccination up to 8 months
Any exacerbation of pre-existing chronic obstructive pulmonary disease	≥14 days after vaccination up to 8 months
Any exacerbation of pre-existing chronic obstructive pulmonary disease (alternate definition)	≥14 days after vaccination up to 8 months
Severe exacerbation of pre-existing chronic obstructive pulmonary disease	≥14 days after vaccination up to 8 months
Severe exacerbation of pre-existing chronic obstructive pulmonary disease (alternate definition)	≥14 days after vaccination up to 8 months
Any exacerbation of pre-existing asthma	≥14 days after vaccination up to 8 months
Any exacerbation of pre-existing asthma (alternate definition)	≥14 days after vaccination up to 8 months
Severe exacerbation of pre-existing asthma	≥14 days after vaccination up to 8 months
Severe exacerbation of pre-existing asthma (alternate definition)	≥14 days after vaccination up to 8 months
Exacerbation of pre-existing heart failure	≥14 days after vaccination up to 8 months
Exacerbation of pre-existing heart failure (alternate definition)	≥14 days after vaccination up to 8 months
Hospitalization for pericarditis	≥14 days after vaccination up to 8 months
Hospitalization for myocarditis	≥14 days after vaccination up to 8 months
New-onset dementia	≥14 days after vaccination up to 8 months

Collaborators and Investigators

• Sponsor: Tor Biering-Sørensen
• Collaborators: Sanofi; Hospital Clinico Universitario de Santiago
• Investigators: Study Chair: Tor Biering-Sørensen, MD, MSc, MPH, PhD, Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2025
• Primary Completion (Actual): May 31, 2025
• Study Completion (Actual): August 31, 2025

Study Registration Dates

• First Submitted: July 12, 2024
• First Submitted That Met QC Criteria: July 12, 2024
• First Posted (Actual): July 18, 2024

Study Record Updates

• Last Update Posted (Estimated): September 12, 2025
• Last Update Submitted That Met QC Criteria: September 8, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Pneumonia; Influenza; Cardiovascular; Vaccination; Registry; Respiratory; Meta-analysis; Pragmatic
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Influenza, Human; Pneumonia; Biological Products; Complex Mixtures; Vaccines; Viral Vaccines; Influenza Vaccines
• Other Study ID Numbers: DANFLU/GALFLU pooled analysis

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In each trial, baseline and endpoint data will be collected from administrative health registries, which are subject to local legislation and can only be made available to a third party under certain conditions. Please contact the sponsor in case of any inquiries.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No