A Pragmatic Randomized Feasibility Trial of Influenza Vaccines — showed it was feasible to conduct a quadrivalent vaccines comparison, based on registry-based data 


institute for health transformation (inhealth)


Joaquim Cardoso MSc
Founder, CEO and Senior Advisor
January 24, 2023



EXECUTIVE SUMMARY


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. 

  • Such a trial would potentially require a sample size of more than 200,000 participants

  • Because of the large sample size required, such a trial will need to incorporate innovative, pragmatic elements.
  • Given the high costs and regulatory requirements of conducting traditional randomized trials,17,18 pragmatic approaches are important to consider.

The use of health data routinely obtained in a universal public health care system and captured in administrative registries as the primary data source in randomized trials has several advantages:


  • it increases the feasibility of conducting large-scale trials by reducing the administrative burden placed on investigators,

  • minimizes loss to follow-up,

  • and facilitates streamlined trial design.19,20


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).

CONCLUSIONS


  • Conducting a pragmatic randomized trial of QIV-HD versus QIV-SD using existing infrastructure and registry-based data collection was feasible. 

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.


Conducting 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.)

INFOGRAPHIC









ORIGINAL PUBLICATION







A Pragmatic Randomized Feasibility Trial of Influenza Vaccines


NEJM Evidence


Niklas Dyrby Johansen, M.D.1,2, Daniel Modin, M.B.1,2, Joshua Nealon, Ph.D.3, Sandrine Samson, Ph.D.4, Camille Salamand, M.Sc.4, Matthew M. Loiacono, Ph.D.5, Carsten Schade Larsen, M.D., D.M.Sc.6, Anne Marie Reimer Jensen, M.D.1,2, Nino Emanuel Landler, M.D.1,2, Brian L. Claggett, Ph.D.7, Scott D. Solomon, M.D.7, Martin J. Landray, Ph.D.8,9, Gunnar H. Gislason, M.D., Ph.D.1,10,11,12, Lars Køber, M.D., D.M.Sc.10,13, Jens Ulrik Stæhr Jensen, M.D., Ph.D.14, Pradeesh Sivapalan, M.D., Ph.D.14, Lasse Skafte Vestergaard, M.D., Ph.D.15, Palle Valentiner-Branth, M.D., Ph.D.15, Tyra Grove Krause, M.D., Ph.D.15, and Tor Biering-Sørensen, M.D., Ph.D., M.P.H.1,2


January 23, 2023





Introduction


Influenza vaccination effectively reduces the incidence of influenza infection and influenza-related morbidity and mortality,1–3 and annual vaccination of persons aged 65 years and older as well as other high-risk groups is widely recommended.4,5 


In a prior randomized trial, high-dose (HD) trivalent influenza vaccine reduced the incidence of laboratory-confirmed influenza illness by an additional 24.2% compared with standard-dose trivalent influenza vaccine,6 and recent meta-analyses have similarly suggested consistent benefits in the relative effectiveness (rVE) of HD influenza vaccines compared with standard-dose vaccines.7,8 HD quadrivalent influenza vaccines (QIV-HD) are approved for use in persons 60 or 65 years of age and older, depending on the country, but are not yet widely implemented. 

Currently, there is no clinically directive evidence from an individually randomized trial that has evaluated the rVE of QIV-HD versus standard-dose quadrivalent influenza vaccine (QIV-SD) against severe clinical outcomes such as hospitalizations and mortality in the general older population; such evidence would allow for an assessment of the full public health value of QIV-HD. 

Because such a trial would potentially require a sample size of more than 200,000 participants,9 we designed the DANFLU-1 (Feasibility of Randomizing Danish Citizens Aged 65–79 Years to High-Dose Quadrivalent Influenza Vaccine vs. Standard-Dose Quadrivalent Influenza Vaccine in a Pragmatic Registry-Based Setting) trial to evaluate the feasibility of integrating an individually randomized study into routine seasonal influenza vaccination practice and using administrative health registries for data collection.


Because such a trial would potentially require a sample size of more than 200,000 participants,9 we designed the DANFLU-1 (Feasibility of Randomizing Danish Citizens Aged 65–79 Years to High-Dose Quadrivalent Influenza Vaccine vs. Standard-Dose Quadrivalent Influenza Vaccine in a Pragmatic Registry-Based Setting) trial …

… to evaluate the feasibility of integrating an individually randomized study into routine seasonal influenza vaccination practice and using administrative health registries for data collection.

Methods & other sections


See the original publication (this is an excerpt version)

Results


See the original publication



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Discussion


In this pragmatic randomized feasibility trial, we enrolled more than 12,000 patients in 7 weeks. 


The number of enrolled participants was lower than the planned sample size of 40,000, one possible reason being delays in the obtainment of regulatory approvals, which meant that recruitment was initiated only 7 days before the start of the influenza vaccination period. 

The participation rate of approximately 37% was encouraging when considering that approximately 17% of the Danish population aged 65 years and older (200,000 of 1.2 million) would have to be enrolled in a potential fully powered trial to meet the sample size requirement.9 

Registry-based data collection and linkage were feasible, and they allowed for the accurate and timely assessment of baseline characteristics, outcomes, and safety during the conduct of the trial with complete follow-up data available for more than 99.9% of participants. 

The trial design enabled successful randomization between treatment groups, as well as assessment of the representativeness of the trial population compared with the general population on the basis of both baseline characteristics and outcome incidence rates. 

This trial was not powered to assess clinical outcomes. 

Our findings of a lower incidence of hospitalization for influenza or pneumonia and all-cause mortality in the QIV-HD group compared with the QIV-SD group require confirmation in a fully powered trial.



This individually randomized trial was conducted relying solely on the nationwide Danish administrative health registries for the collection of baseline, outcome, and safety data


By integrating the gold standard of randomization into routine vaccination practice, it was possible to efficiently conduct a large-scale randomized trial in a real-world setting. 

Given the high costs and regulatory requirements of conducting traditional randomized trials,17,18 pragmatic approaches are important to consider. 

In addition, such approaches may increase external validity by potentially improving the representativeness of trial populations relative to traditional clinical trials.


By integrating the gold standard of randomization into routine vaccination practice, it was possible to efficiently conduct a large-scale randomized trial in a real-world setting.



The use of health data routinely obtained in a universal public health care system and captured in administrative registries as the primary data source in randomized trials has several advantages:


  • it increases the feasibility of conducting large-scale trials by reducing the administrative burden placed on investigators, 
  • minimizes loss to follow-up, 
  • and facilitates streamlined trial design.19,20 

Using prespecified definitions that are based on administrative coding may improve consistency and reduce ascertainment bias in the assessment of baseline characteristics and outcomes, and allows for a comparison of the trial population with the corresponding real-world population using the same definitions, facilitating the process of assessing the external validity of a trial. 


Although the use of routine health data can also pose substantial risks, including misclassification and underreporting, these risks would be expected to be equally distributed across randomized arms.19 

The Danish administrative health registries have been widely used for observational studies and are generally well validated, in particular within the cardiovascular domain where most incident events have positive predictive values of more than 90%21; however, even within the cardiovascular domain, the heart failure diagnosis has previously been shown to be underreported.22 

Additional validation work is warranted to examine how the registries perform as the primary data source in a randomized trial setting.


The Danish administrative health registries have been widely used for observational studies and are generally well validated, in particular within the cardiovascular domain where most incident events have positive predictive values of more than 90%21; …

…however, even within the cardiovascular domain, the heart failure diagnosis has previously been shown to be underreported.22


Baseline characteristics were similar between the trial population and the overall Danish population, supporting the generalizability of the findings


End point incidence rates were between 12% and 68% lower in the trial population, which may be explained, in part, by a 100% vaccination rate in the trial population compared with 77.8% in the general Danish population aged 65 to 81 years.23 

In addition, recruiting individuals already seeking vaccination may have introduced a healthy user effect, as individuals accepting vaccination may be healthier and exhibit different patterns of health care–seeking behavior (e.g., increased use of preventive care) than nonvaccinees24; however, these data provide an estimate for the generalizability of the findings and may be used to adjust expected event rates calculated from registry data for future trials. 

Other studies have made similar comparisons to registry populations and excluded patients25–27; however, their results are not directly comparable to ours because of very different trial populations and designs.


In our trial, the observed rVE point estimates for QIV-HD compared with QIV-SD against hospitalization for influenza or pneumonia and all-cause mortality were large; however, the relatively wide CIs around the point estimates reflect the fact that the study was not powered for these outcomes. 


These findings were comparable to others found in the literature, however. 


In an article examining SAE rates in the 2015 trial by DiazGranados et al.,12 a trivalent HD vaccine reduced serious pneumonia by 39.8% (95% CI, 19.3 to 55.1) and all-cause hospitalization by 6.9% (95% CI, 0.5 to 12.8) compared with a trivalent standard-dose vaccine. 

These effect sizes are comparable to those observed in our study, with the previously reported 39.8% reduction in serious pneumonia contained in the 95% CI for hospitalization for influenza or pneumonia and the 6.9% reduction in all-cause hospitalization matching the trend observed in our trial. 

A recent meta-analysis of predominantly observational studies showed consistently superior protection of HD versus standard-dose vaccines over 10 seasons and in more than 34 million people.8


Another individually randomized trial that compared the rVE of HD versus standard-dose vaccines against hospitalizations and mortality was the INVESTED (Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure) trial.28 


This trial investigated the effect of a trivalent HD vaccine compared with QIV-SD on a primary composite end point of all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease. 

No significant difference was found in the incidence of the primary end point in a study population that differed substantially from our general population sample. 

The IAMI (Influenza Vaccination After Myocardial Infarction) trial reported a 28% reduction in the composite primary end point of all-cause death, myocardial infarction, or stent thrombosis with influenza vaccination versus placebo in a population of mostly post–myocardial infarction patients.29 

This conflicts with our findings with regard to cardiovascular end points, but our study was not powered for clinical outcomes and compared two different vaccine types — a very different comparison than evaluating vaccination against placebo.


Of interest, Danish influenza surveillance data for the 2021–2022 influenza season indicated no observable vaccine effectiveness against the circulating influenza A (H3N2) strain with quadrivalent influenza vaccines in adults older than age 45 years.30 


Despite this trial not being powered to assess clinical end points, our data still suggest a possible benefit with QIV-HD compared with QIV-SD during this influenza season, potentially supporting the previously proposed idea of nonspecific immunomodulatory effects of influenza vaccination independent of the prevention of influenza infection.31,32


Despite this trial not being powered to assess clinical end points, our data still suggest a possible benefit with QIV-HD compared with QIV-SD during this influenza season, potentially supporting the previously proposed idea of nonspecific immunomodulatory effects of influenza vaccination independent of the prevention of influenza infection.31,32


The current study has several potential limitations. 


First, it was a feasibility study, which was not powered to assess clinical outcomes and, therefore, the rVE estimates are based on relatively few events. 

The observed reductions in the incidence of hospitalization for influenza or pneumonia and all-cause mortality among those vaccinated with QIV-HD require confirmation in a larger, fully powered trial with adequate control of type I error.

Second, as a result of the pragmatic nature of the trial, no systematic laboratory testing for influenza was performed. 

Nonetheless, despite the absence of laboratory confirmation, by virtue of randomization, any differences observed between groups can effectively be attributed to treatment. 

Third, the trial was open-label; however, the outcomes of hospitalizations and deaths may be less affected by knowledge of treatment group assignment than more subjective outcomes. 

Fourth, there was no adjudication of clinical outcomes, which were based solely on administrative health data; however, data from several large-scale cardiovascular trials and reviews indicate that adjudication might not alter effect estimates from randomized trials,33–37 and using routine health data might increase the generalizability of the results. 

Fifth, no data on race and/or ethnicity were available. Because the study was conducted in Denmark, the study sample would be expected to be predominantly White.

Sixth, the trial was conducted during only one influenza season, precluding comparisons across multiple influenza seasons with different circulating strains or accounting for the possible differential impact of Covid-19 restrictions. 

Seventh, the vaccination provider’s database of prior vaccinees was based on email addresses only and, therefore, no identifier was available for us to distinguish the invitees in the registries and compare these with the recruited trial population. 

We were able, however, to show the comparability of the trial population to the overall Danish population in the same age group.


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Conclusions


Conducting a pragmatic randomized trial of QIV-HD versus QIV-SD using existing infrastructure for recruitment, inclusion, randomization, and vaccination and relying solely on registry-based data collection was feasible


The findings of a lower incidence of hospitalization for influenza or pneumonia and all-cause mortality in the QIV-HD group compared with QIV-SD require confirmation in a future fully powered trial.



References & additional information


See the original publication


About the authors & affiliations


  • Niklas Dyrby Johansen, M.D.1,2,
  • Daniel Modin, M.B.1,2,
  • Joshua Nealon, Ph.D.3,
  • Sandrine Samson, Ph.D.4,
  • Camille Salamand, M.Sc.4,
  • Matthew M. Loiacono, Ph.D.5,
  • Carsten Schade Larsen, M.D., D.M.Sc.6,
  • Anne Marie Reimer Jensen, M.D.1,2,
  • Nino Emanuel Landler, M.D.1,2,
  • Brian L. Claggett, Ph.D.7,
  • Scott D. Solomon, M.D.7,
  • Martin J. Landray, Ph.D.8,9,
  • Gunnar H. Gislason, M.D., Ph.D.1,10,11,12,
  • Lars Køber, M.D., D.M.Sc.10,13,
  • Jens Ulrik Stæhr Jensen, M.D., Ph.D.14,
  • Pradeesh Sivapalan, M.D., Ph.D.14,
  • Lasse Skafte Vestergaard, M.D., Ph.D.15,
  • Palle Valentiner-Branth, M.D., Ph.D.15,
  • Tyra Grove Krause, M.D., Ph.D.15, and
  • Tor Biering-Sørensen, M.D., Ph.D., M.P.H.1,2

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  • 1Department of Cardiology, Copenhagen University Hospital–Herlev and Gentofte, Copenhagen
  • 2Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
  • 3School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
  • 4Sanofi, Lyon, France
  • 5Sanofi, Swiftwater, PA
  • 6Department of Clinical Medicine, Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
  • 7Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston
  • 8Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Public Health, University of Oxford, Oxford, United Kingdom
  • 9Big Data Institute, University of Oxford, Oxford, United Kingdom
  • 10Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
  • 11The Danish Heart Foundation, Copenhagen
  • 12The National Institute of Public Health, University of Southern Denmark, Copenhagen
  • 13Department of Cardiology, Copenhagen University Hospital–Rigshospitalet, Copenhagen
  • 14Respiratory Medicine Section, Department of Medicine, Copenhagen University Hospital–Herlev and Gentofte, Copenhagen
  • 15Epidemiological Infectious Disease Preparedness, Statens Serum Institut, Copenhagen

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