A Pragmatic Randomized Feasibility Trial of Influenza Vaccines

Niklas Dyrby Johansen; Daniel Modin; Joshua Nealon; Sandrine Samson; Camille Salamand; Matthew M. Loiacono; Carsten Schade Larsen; Anne Marie Reimer Jensen; Nino Emanuel Landler; Brian L. Claggett; Scott D. Solomon; Martin J. Landray; Gunnar H. Gislason; Lars Køber; Jens Ulrik Stæhr Jensen; Pradeesh Sivapalan; Lasse Skafte Vestergaard; Palle Valentiner-branth; Tyra Grove Krause; Tor Biering-sørensen

doi:10.1056/EVIDoa2200206

A Pragmatic Randomized Feasibility Trial of Influenza Vaccines

Niklas Dyrby Johansen, Daniel Modin, Joshua Nealon, Sandrine Samson, Camille Salamand, Matthew M. Loiacono, Carsten Schade Larsen, Anne Marie Reimer Jensen, Nino Emanuel Landler, Brian L. Claggett, Scott D. Solomon, Martin J. Landray, Gunnar H. Gislason, Lars Køber, Jens Ulrik Stæhr Jensen, Pradeesh Sivapalan, Lasse Skafte Vestergaard, Palle Valentiner-branth, Tyra Grove Krause, Tor Biering-sørensen

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Background
The relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccines (QIV-HD) versus standard-dose quadrivalent influenza vaccines (QIV-SD) against hospitalizations and mortality in the general older population has not been evaluated in an individually randomized trial. Because of the large sample size required, such a trial will need to incorporate innovative, pragmatic elements.

Methods
We conducted a pragmatic, open-label, active-controlled, randomized feasibility trial in Danish citizens aged 65 to 79 years during the 2021–2022 influenza season. Participants were randomly assigned 1:1 to receive QIV-HD or QIV-SD. Randomization was integrated into routine vaccination practice, and the trial relied solely on nationwide administrative health registries for data collection. Outcomes consisted of a feasibility assessment and descriptive rVE estimates.
Results
We invited 34,000 persons to participate. A total of 12,477 randomly assigned participants were included in the final analyses. Mean (±SD) age was 71.7±3.9 years, and 5877 (47.1%) were women. Registry-based data collection was feasible, with complete follow-up data for 99.9% of participants. Baseline characteristics were comparable to those of the overall Danish population aged 65 to 79 years. The incidence of hospitalization for influenza or pneumonia was 10 (0.2%) of 6245 in the QIV-HD group and 28 (0.4%) of 6232 in the QIV-SD group (rVE, 64.4%; 95% confidence interval, 24.4 to 84.6). All-cause death occurred in 21 (0.3%) and 41 (0.7%) participants in the QIV-HD and QIV-SD groups, respectively (rVE, 48.9%; 95% confidence interval, 11.5 to 71.3).
ConclusionsConducting a pragmatic randomized trial of QIV-HD versus QIV-SD using existing infrastructure and registry-based data collection was feasible. The findings of lower incidence of hospitalization for influenza or pneumonia and all-cause mortality in the QIV-HD group compared with the QIV-SD group require replication in a future, fully powered trial. (Funded by Sanofi; ClinicalTrials.gov number, NCT05048589.)

Original language	English
Journal	NEJM Evidence
Volume	2
Issue number	2
Number of pages	11
ISSN	2766-5526
DOIs	https://doi.org/10.1056/EVIDoa2200206
Publication status	Published - 2023

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10.1056/EVIDoa2200206

Cite this

Johansen, N. D., Modin, D., Nealon, J., Samson, S., Salamand, C., Loiacono, M. M., Larsen, C. S., Jensen, A. M. R., Landler, N. E., Claggett, B. L., Solomon, S. D., Landray, M. J., Gislason, G. H., Køber, L., Jensen, J. U. S., Sivapalan, P., Vestergaard, L. S., Valentiner-branth, P., Krause, T. G., & Biering-sørensen, T. (2023). A Pragmatic Randomized Feasibility Trial of Influenza Vaccines. NEJM Evidence, 2(2). https://doi.org/10.1056/EVIDoa2200206

A Pragmatic Randomized Feasibility Trial of Influenza Vaccines. / Johansen, Niklas Dyrby; Modin, Daniel; Nealon, Joshua; Samson, Sandrine; Salamand, Camille; Loiacono, Matthew M.; Larsen, Carsten Schade; Jensen, Anne Marie Reimer; Landler, Nino Emanuel; Claggett, Brian L.; Solomon, Scott D.; Landray, Martin J.; Gislason, Gunnar H.; Køber, Lars ; Jensen, Jens Ulrik Stæhr; Sivapalan, Pradeesh; Vestergaard, Lasse Skafte; Valentiner-branth, Palle; Krause, Tyra Grove ; Biering-sørensen, Tor.

In: NEJM Evidence, Vol. 2, No. 2, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Johansen, ND, Modin, D, Nealon, J, Samson, S, Salamand, C, Loiacono, MM, Larsen, CS, Jensen, AMR, Landler, NE, Claggett, BL, Solomon, SD, Landray, MJ, Gislason, GH , Køber, L , Jensen, JUS, Sivapalan, P, Vestergaard, LS, Valentiner-branth, P, Krause, TG & Biering-sørensen, T 2023, 'A Pragmatic Randomized Feasibility Trial of Influenza Vaccines', NEJM Evidence, vol. 2, no. 2. https://doi.org/10.1056/EVIDoa2200206

Johansen, Niklas Dyrby ; Modin, Daniel ; Nealon, Joshua ; Samson, Sandrine ; Salamand, Camille ; Loiacono, Matthew M. ; Larsen, Carsten Schade ; Jensen, Anne Marie Reimer ; Landler, Nino Emanuel ; Claggett, Brian L. ; Solomon, Scott D. ; Landray, Martin J. ; Gislason, Gunnar H. ; Køber, Lars ; Jensen, Jens Ulrik Stæhr ; Sivapalan, Pradeesh ; Vestergaard, Lasse Skafte ; Valentiner-branth, Palle ; Krause, Tyra Grove ; Biering-sørensen, Tor. / A Pragmatic Randomized Feasibility Trial of Influenza Vaccines. In: NEJM Evidence. 2023 ; Vol. 2, No. 2.

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title = "A Pragmatic Randomized Feasibility Trial of Influenza Vaccines",

abstract = "BackgroundThe relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccines (QIV-HD) versus standard-dose quadrivalent influenza vaccines (QIV-SD) against hospitalizations and mortality in the general older population has not been evaluated in an individually randomized trial. Because of the large sample size required, such a trial will need to incorporate innovative, pragmatic elements.MethodsWe conducted a pragmatic, open-label, active-controlled, randomized feasibility trial in Danish citizens aged 65 to 79 years during the 2021–2022 influenza season. Participants were randomly assigned 1:1 to receive QIV-HD or QIV-SD. Randomization was integrated into routine vaccination practice, and the trial relied solely on nationwide administrative health registries for data collection. Outcomes consisted of a feasibility assessment and descriptive rVE estimates.ResultsWe invited 34,000 persons to participate. A total of 12,477 randomly assigned participants were included in the final analyses. Mean (±SD) age was 71.7±3.9 years, and 5877 (47.1%) were women. Registry-based data collection was feasible, with complete follow-up data for 99.9% of participants. Baseline characteristics were comparable to those of the overall Danish population aged 65 to 79 years. The incidence of hospitalization for influenza or pneumonia was 10 (0.2%) of 6245 in the QIV-HD group and 28 (0.4%) of 6232 in the QIV-SD group (rVE, 64.4%; 95% confidence interval, 24.4 to 84.6). All-cause death occurred in 21 (0.3%) and 41 (0.7%) participants in the QIV-HD and QIV-SD groups, respectively (rVE, 48.9%; 95% confidence interval, 11.5 to 71.3).ConclusionsConducting a pragmatic randomized trial of QIV-HD versus QIV-SD using existing infrastructure and registry-based data collection was feasible. The findings of lower incidence of hospitalization for influenza or pneumonia and all-cause mortality in the QIV-HD group compared with the QIV-SD group require replication in a future, fully powered trial. (Funded by Sanofi; ClinicalTrials.gov number, NCT05048589.)",

author = "Johansen, {Niklas Dyrby} and Daniel Modin and Joshua Nealon and Sandrine Samson and Camille Salamand and Loiacono, {Matthew M.} and Larsen, {Carsten Schade} and Jensen, {Anne Marie Reimer} and Landler, {Nino Emanuel} and Claggett, {Brian L.} and Solomon, {Scott D.} and Landray, {Martin J.} and Gislason, {Gunnar H.} and Lars K{\o}ber and Jensen, {Jens Ulrik St{\ae}hr} and Pradeesh Sivapalan and Vestergaard, {Lasse Skafte} and Palle Valentiner-branth and Krause, {Tyra Grove} and Tor Biering-s{\o}rensen",

year = "2023",

doi = "10.1056/EVIDoa2200206",

language = "English",

volume = "2",

journal = "NEJM Evidence",

issn = "2766-5526",

publisher = "Massachussetts Medical Society",

number = "2",

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TY - JOUR

T1 - A Pragmatic Randomized Feasibility Trial of Influenza Vaccines

AU - Johansen, Niklas Dyrby

AU - Modin, Daniel

AU - Nealon, Joshua

AU - Samson, Sandrine

AU - Salamand, Camille

AU - Loiacono, Matthew M.

AU - Larsen, Carsten Schade

AU - Jensen, Anne Marie Reimer

AU - Landler, Nino Emanuel

AU - Claggett, Brian L.

AU - Solomon, Scott D.

AU - Landray, Martin J.

AU - Gislason, Gunnar H.

AU - Køber, Lars

AU - Jensen, Jens Ulrik Stæhr

AU - Sivapalan, Pradeesh

AU - Vestergaard, Lasse Skafte

AU - Valentiner-branth, Palle

AU - Krause, Tyra Grove

AU - Biering-sørensen, Tor

PY - 2023

Y1 - 2023

N2 - BackgroundThe relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccines (QIV-HD) versus standard-dose quadrivalent influenza vaccines (QIV-SD) against hospitalizations and mortality in the general older population has not been evaluated in an individually randomized trial. Because of the large sample size required, such a trial will need to incorporate innovative, pragmatic elements.MethodsWe conducted a pragmatic, open-label, active-controlled, randomized feasibility trial in Danish citizens aged 65 to 79 years during the 2021–2022 influenza season. Participants were randomly assigned 1:1 to receive QIV-HD or QIV-SD. Randomization was integrated into routine vaccination practice, and the trial relied solely on nationwide administrative health registries for data collection. Outcomes consisted of a feasibility assessment and descriptive rVE estimates.ResultsWe invited 34,000 persons to participate. A total of 12,477 randomly assigned participants were included in the final analyses. Mean (±SD) age was 71.7±3.9 years, and 5877 (47.1%) were women. Registry-based data collection was feasible, with complete follow-up data for 99.9% of participants. Baseline characteristics were comparable to those of the overall Danish population aged 65 to 79 years. The incidence of hospitalization for influenza or pneumonia was 10 (0.2%) of 6245 in the QIV-HD group and 28 (0.4%) of 6232 in the QIV-SD group (rVE, 64.4%; 95% confidence interval, 24.4 to 84.6). All-cause death occurred in 21 (0.3%) and 41 (0.7%) participants in the QIV-HD and QIV-SD groups, respectively (rVE, 48.9%; 95% confidence interval, 11.5 to 71.3).ConclusionsConducting a pragmatic randomized trial of QIV-HD versus QIV-SD using existing infrastructure and registry-based data collection was feasible. The findings of lower incidence of hospitalization for influenza or pneumonia and all-cause mortality in the QIV-HD group compared with the QIV-SD group require replication in a future, fully powered trial. (Funded by Sanofi; ClinicalTrials.gov number, NCT05048589.)

AB - BackgroundThe relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccines (QIV-HD) versus standard-dose quadrivalent influenza vaccines (QIV-SD) against hospitalizations and mortality in the general older population has not been evaluated in an individually randomized trial. Because of the large sample size required, such a trial will need to incorporate innovative, pragmatic elements.MethodsWe conducted a pragmatic, open-label, active-controlled, randomized feasibility trial in Danish citizens aged 65 to 79 years during the 2021–2022 influenza season. Participants were randomly assigned 1:1 to receive QIV-HD or QIV-SD. Randomization was integrated into routine vaccination practice, and the trial relied solely on nationwide administrative health registries for data collection. Outcomes consisted of a feasibility assessment and descriptive rVE estimates.ResultsWe invited 34,000 persons to participate. A total of 12,477 randomly assigned participants were included in the final analyses. Mean (±SD) age was 71.7±3.9 years, and 5877 (47.1%) were women. Registry-based data collection was feasible, with complete follow-up data for 99.9% of participants. Baseline characteristics were comparable to those of the overall Danish population aged 65 to 79 years. The incidence of hospitalization for influenza or pneumonia was 10 (0.2%) of 6245 in the QIV-HD group and 28 (0.4%) of 6232 in the QIV-SD group (rVE, 64.4%; 95% confidence interval, 24.4 to 84.6). All-cause death occurred in 21 (0.3%) and 41 (0.7%) participants in the QIV-HD and QIV-SD groups, respectively (rVE, 48.9%; 95% confidence interval, 11.5 to 71.3).ConclusionsConducting a pragmatic randomized trial of QIV-HD versus QIV-SD using existing infrastructure and registry-based data collection was feasible. The findings of lower incidence of hospitalization for influenza or pneumonia and all-cause mortality in the QIV-HD group compared with the QIV-SD group require replication in a future, fully powered trial. (Funded by Sanofi; ClinicalTrials.gov number, NCT05048589.)

U2 - 10.1056/EVIDoa2200206

DO - 10.1056/EVIDoa2200206

M3 - Journal article

C2 - 38320035

VL - 2

JO - NEJM Evidence

JF - NEJM Evidence

SN - 2766-5526

IS - 2

ER -