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| ID | Type | Description | Link |
|---|---|---|---|
| 2022-500657-17-00 | Other Identifier | EU Clinical Trial Number |
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| Name | Class |
|---|---|
| Sanofi | INDUSTRY |
| Statens Serum Institut | OTHER |
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The purpose of this pragmatic randomized trial is to evaluate the relative vaccine effectiveness of high-dose quadrivalent influenza vaccine (QIV-HD) vs. standard-dose quadrivalent influenza vaccine (QIV-SD) in older adults. Participants will be randomized 1:1 to either QIV-HD or QIV-SD.
The study is a pragmatic, registry-based, open-label, active-controlled, individually randomized trial. The Danish nationwide administrative health registries will be used for data collection including baseline information, follow-up data, and safety monitoring. The study aims to randomize 339,700 participants over 3 influenza seasons. In each season, participants will be individually randomized 1:1 to receive either QIV-HD or QIV-SD. During the 2023/2024 and 2024/2025 seasons, up to 12,000 participants will be enrolled in a sub-cohort where participants are asked to perform home self-swabs and answer symptom questionnaires in case of influenza-like illness to enable further assessment of the impact of QIV-HD vs. QIV-SD on patient-reported outcomes among individuals with influenza-like illness and laboratory-confirmed influenza.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High-Dose Quadrivalent Influenza Vaccine | Experimental | QIV-HD single injection at Day 0 |
|
| Standard-Dose Quadrivalent Influenza Vaccine | Active Comparator | QIV-SD single injection at Day 0 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| High-Dose Quadrivalent Influenza Vaccine | Biological | For this arm, the high-dose quadrivalent influenza vaccine Efluelda®/Fluzone® High-Dose Quadrivalent will be used. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Hospitalization for influenza or pneumonia | ≥14 days after vaccination up to 8 months |
| Measure | Description | 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 | |
| Measure | Description | 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tor Biering-Sørensen, MD, PhD, MPH | Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte | Hellerup | Capital Region | 2900 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41525066 | Derived | Nielsen AB, Johansen ND, Modin D, Loiacono MM, Harris RC, Dufournet M, Larsen CS, Larsen L, Wiese L, Dalager-Pedersen M, Claggett BL, Janstrup KH, Bartholdy KV, Bernholm KF, Borchsenius JIH, Davidovski FS, Davodian LW, Dons M, Duus LS, Espersen C, Fussing FH, Jensen AMR, Landler NE, Langhoff ACF, Lassen MCH, Ottosen CI, Sengelov M, Skaarup KG, Pareek M, Muller-Wieland D, Solomon SD, Landray MJ, Gislason GH, Kober L, Sivapalan P, Martel CJ, Jensen JUS, Biering-Sorensen T. High-Dose vs Standard-Dose Influenza Vaccine in Older Adults With Diabetes: A Secondary Analysis of the DANFLU-2 Randomized Clinical Trial. JAMA Intern Med. 2026 Mar 1;186(3):311-320. doi: 10.1001/jamainternmed.2025.7286. | |
| 40888720 |
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In this trial, baseline and endpoint data will be collected from Danish administrative health registries, which are subject to Danish legislation and can only be made available to a third party under certain conditions. Please contact the sponsor-investigator in case of any inquiries.
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| Standard-Dose Quadrivalent Influenza Vaccine | Biological | Any standard-dose quadrivalent influenza vaccine administered in the Danish governmental influenza vaccine program may be used. |
|
|
| 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 |
| 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 |
| Laboratory-confirmed influenza hospitalization | ≥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 |
| Danske Lægers Vaccinations Service | Søborg | 2860 | Denmark |
| Derived |
| Johansen ND, Modin D, Loiacono MM, Harris RC, Dufournet M, Larsen CS, Larsen L, Wiese L, Dalager-Pedersen M, Claggett BL, Janstrup KH, Bartholdy KV, Bernholm KF, Borchsenius JIH, Davidovski FS, Davodian LW, Dons M, Duus LS, Espersen C, Fussing FH, Jensen AMR, Landler NE, Langhoff ACF, Lassen MCH, Nielsen AB, Ottosen CI, Sengelov M, Skaarup KG, Solomon SD, Landray MJ, Gislason GH, Kober L, Ralfkiaer L, Nealon J, Sivapalan P, Martel CJ, Jensen JUS, Biering-Sorensen T. High-Dose Influenza Vaccine Effectiveness against Hospitalization in Older Adults. N Engl J Med. 2025 Dec 11;393(23):2291-2302. doi: 10.1056/NEJMoa2509907. Epub 2025 Aug 30. |
| 40884442 | Derived | Johansen ND, Modin D, Loiacono MM, Harris RC, Dufournet M, Larsen CS, Larsen L, Wiese L, Dalager-Pedersen M, Claggett BL, Janstrup KH, Bartholdy KV, Bernholm KF, Borchsenius JIH, Davidovski FS, Davodian LW, Dons M, Duus LS, Espersen C, Fussing FH, Jensen AMR, Landler NE, Langhoff ACF, Lassen MCH, Nielsen AB, Ottosen CI, Sengelov M, Skaarup KG, Pareek M, Solomon SD, Landray MJ, Gislason GH, Kober L, Sivapalan P, Martel CJ, Jensen JUS, Biering-Sorensen T. High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial. JAMA Cardiol. 2025 Nov 1;10(11):1186-1194. doi: 10.1001/jamacardio.2025.3460. |
| 40884411 | Derived | Skaarup KG, Johansen ND, Modin D, Loiacono MM, Harris RC, Dufournet M, Larsen CS, Larsen L, Wiese L, Dalager-Pedersen M, Claggett BL, Bartholdy KV, Bernholm KF, Borchsenius JIH, Davidovski FS, Davodian LW, Dons M, Duus LS, Espersen C, Fussing FH, Jensen AMR, Landler NE, Langhoff ACF, Lassen MCH, Nielsen AB, Ottosen CI, Sengelov M, Solomon SD, Landray MJ, Gislason GH, Kober L, Sivapalan P, Martel CJ, Jensen JUS, Mebazaa A, Biering-Sorensen T. High-Dose Versus Standard-Dose Influenza Vaccine in Heart Failure: A Prespecified Analysis of the DANFLU-2 Trial. Circ Heart Fail. 2025 Nov;18(11):e013678. doi: 10.1161/CIRCHEARTFAILURE.125.013678. Epub 2025 Aug 30. |
| 40844659 | Derived | Davidovski FS, Skaarup KG, Johansen ND, Modin D, Shaikh N, Bartelt-Hofer J, Loiacono MM, Harris RC, Larsen CS, Larsen L, Wiese L, Dalager-Pedersen M, Jessen R, Steenhard N, Claggett BL, Solomon SD, Kober L, Sivapalan P, Jensen JUS, Martel CJ, Biering-Sorensen T. Patient-reported outcomes and home-based self-swabs for influenza-like illness events - lessons learned from the 2023/2024 DANFLU-2 Homeswab PRO substudy. J Patient Rep Outcomes. 2025 Aug 22;9(1):108. doi: 10.1186/s41687-025-00936-8. |
| 40749884 | Derived | Johansen ND, Modin D, Loiacono MM, Harris RC, Dufournet M, Larsen CS, Larsen L, Wiese L, Dalager-Pedersen M, Claggett BL, Skaarup KG, Davidovski FS, Solomon SD, Landray MJ, Gislason GH, Kober L, Sivapalan P, Martel CJ, Jensen JUS, Biering-Sorensen T. A pragmatic individually randomized trial to evaluate the effectiveness of high-dose vs standard-dose influenza vaccine in older adults: Rationale and design of the DANFLU-2 trial. Am Heart J. 2026 Jan;291:186-198. doi: 10.1016/j.ahj.2025.07.069. Epub 2025 Jul 30. |
| ID | Term |
|---|---|
| D007251 | Influenza, Human |
| D011014 | Pneumonia |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D009976 | Orthomyxoviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012140 | Respiratory Tract Diseases |
| D008171 | Lung Diseases |
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| ID | Term |
|---|---|
| D007252 | Influenza Vaccines |
| ID | Term |
|---|---|
| D014765 | Viral Vaccines |
| D014612 | Vaccines |
| D001688 | Biological Products |
| D045424 | Complex Mixtures |
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