TARGET-EU: Comparison of single-device vilanterol/fluticasone furoate with other single-device inhaled corticosteroid and long-acting beta agonist combinations in the risk of pneumonia in adolescents with asthma

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  (R03AK10) vilanterol and fluticasone furoate

  vilanterol and fluticasone furoate
• Medical condition to be studied:
  Asthma

Population studied

• Short description of the study population:
  This study is conducted using routinely collected electronic health records from 2014 to 2023. The study is set primarily in primary care, drawing on longitudinal data from general practices with linkage to hospital data. Data are sourced from two European countries, the United Kingdom (Clinical Practice Research Datalink [CPRD]) and Finland (Finnish national registries), providing population-based and representative coverage of real-world clinical care. ; ; The study population will consist of adolescent asthma patients, age 12-17 who initiate vilanterol+fluticasone furoate treatment V+FF or other single-device inhaled corticosteroid+long-acting beta agonist treatment (ICS+LABA) and were on ICS treatment within the year preceding the initiation.
• Age groups:
  • Adolescents (12 to < 18 years)
• Special population of interest:
  Other
• Special population of interest, other:
  Adolescents

Study design details

• Study design:
  This study will emulate a hypothetical target trial using a retrospective, active-comparator, new-user cohort design based on routinely collected electronic health records.
• Main study objective:
  The main objective of this observational cohort study is to assess whether vilanterol+fluticasone increases the risk of pneumonia compared to other single-device inhaled corticosteroid+long-acting beta-2 adrenoceptor (ICS+LABA) combinations in adolescent patients with asthma already treated with ICS.
• Setting:
  This study is conducted using routinely collected electronic health records from 2014 to 2023, reflecting the period of vilanterol-fluticasone furoate use in routine clinical practice. The study is set primarily in primary care, drawing on longitudinal data from general practices with linkage to hospital data. Data are sourced from two European countries, the United Kingdom (Clinical Practice Research Datalink [CPRD]) and Finland, providing population-based and representative coverage of real-world clinical care.
• Comparators:
  The use of an active comparator of other single-device inhaled corticosteroid+long-acting beta agonist treatmentns (ICS+SABA) combination treatments will allow us to compare initiators who are in need of a similar line of therapy and at a similar stage of asthma severity, reducing confounding by indication. Restriction to single-device treatment ensures similar compliance between the treatment groups.
• Outcomes:
  Pneumonia is a severe infection, and its impact on patients with asthma can be particularly harmful due to underlying conditions. Pneumonia also increases the risk of asthma exacerbations in all age groups, and ICS increase the risk of pneumonia also in adolescents. Pneumonia has been included in the pre-specified adverse events in asthma RCTs, but there are no specific estimates on pneumonia risk in the adolescent population. Most pneumonia cases are treated in outpatient settings, therefore we include both in- and outpatient diagnoses as well as data from primary and secondary healthcare.
• Data analysis plan:
  The analyses are conducted within a target trial emulation framework to estimate the effect of initiating vilanterol+fluticasone furoate treatment V+FF or other single-device inhaled corticosteroid+long-acting beta agonist (ICS+LABA) combination treatment on the risk of incident pneumonia. ; ; For Estimand 1, the main estimand supporting decision making, the primary causal effect summary measure is the hazard ratio for time to incident pneumonia, estimated using an inverse probability of treatment weighted (IPTW) Cox proportional hazards model. The Cox model will be fitted separately within each data source (Finnish registers and CPRD), and the resulting hazard ratios will be combined using a random-effects meta-analysis; potential sources of heterogeneity will be described qualitatively, including structural differences (e.g., coding systems, population coverage) and measurement differences (e.g., recording practices) and their implications (e.g., residual confounding or misclassification). ; ; Sensitivity analyses will assess robustness of the primary findings to key assumptions, including inverse probability of censoring weighting (IPCW), tipping point analysis, and probabilistic bias analysis for non-differential exposure misclassification.; ; Two supplemental estimands are also defined: Estimand 2, estimating treatment effects using restricted mean survival time (RMST) derived from an IPTW-weighted Weibull accelerated failure time (AFT) model and Estimand 3 (in Finnish data only), investigating time to first pneumonia diagnosis or pneumonia death with same statistical analysis methods as in Estimand 3. In addition, supplemental analyses (e.g., crude and IPTW-adjusted Kaplan–Meier curves, crude Cox models, event counts and incidence rates, propensity score and weight distributions, censoring and intercurrent event patterns, proportional hazards diagnostics and positivity checks) will be conducted to support interpretation of the main analysis.
• Summary results:
  Not yet available