TARGET-EU: Effectiveness of nirsevimab for RSV-lower respiratory tract infection hospitalization in infants ≤12 months of age

Study type

• Study topic:
  Disease /health condition

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

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  NIRSEVIMAB
• Medical condition to be studied:
  Hospitalisation

Population studied

• Short description of the study population:
  In this cohort study we will include infants <12 months of age at exposure and born at ≥29 weeks gestational age who are continuously enrolled since birth in the PEDIANET database starting from January 2023. We restricted the population only to those ≤ 12 months of age because this is the target population for immunization programs implemented and we restricted the population only to those born at or after 29 weeks of gestational age because those born before are usually exposed to palivizumab or might have had a previous prophylaxis with palivizumab and then a prophylaxis also with nirsevimab.; ; Exclusion criteria: ongoing LRTI infection, maternal RSV vaccination during pregnancy, or palivizumab eligibility. ; ; In this study:; - For the exposed group, “time 0” is defined as the date of first receipt of nirsevimab during the study period. This date represents the earliest point at which the individual could reasonably be expected to experience any potential effects associated with the intervention. Anchoring “time 0” at the time of administration ensures that follow-up and outcome ascertainment are appropriately aligned with the biologically plausible period of risk or benefit.; - For the comparator group, “time 0” is defined as the date of receipt of nirsevimab for the matched exposed individual. This matching date is selected to mirror the temporal distribution of cohort entry in the exposed group, thereby minimising biases related to calendar time and seasonality (especially relevant in studies involving respiratory pathogens), as well as temporal changes in healthcare delivery or data capture. At time 0, comparator individuals are required to be alive, eligible, and not yet exposed to nirsevimab. Individuals in the comparator group who subsequently will receive nirsevimab during follow-up will be not contribute data to the study after the nirsevimab administration. To emulate a parallel-arm target trial, matching will be performed without replacement at each index date. Individuals can enter the study only once, at their first eligible index date.; ; Because infants in the unexposed group do not have a treatment administration date, a 1:1 matching procedure will be used to assign a comparable index date (time 0). For each infant receiving nirsevimab, one infant who did not receive nirsevimab will be selected and assigned the same index date, matched on age group at the time of nirsevimab administration (≤3.0 months, >3.0 to ≤6.0 months, and >6.0 months) and calendar week of administration. This matching procedure ensures alignment of follow-up time between exposure groups and accounts for age and calendar time. All subsequent assessments, such as the application of inclusion and exclusion criteria, outcome surveillance, and follow-up duration, are defined relative to this primary temporal anchor.
• Age groups:
  • Neonate

    • Preterm newborn infants (0 – 27 days)
    • Term newborn infants (0 – 27 days)
  • Infants and toddlers (28 days – 23 months)

Study design details

• Study design:
  A cohort design is well suited to emulation of the target trial for interventions such as nirsevimab, where the exposure is fixed at a single point in time (i.e. single administration) rather than repeatedly administered.
• Main study objective:
  The primary objective is to assess nirsevimab effectiveness in preventing RSV-LRTI hospitalization within six months of administration among infants ≤12 months compared to no immunization. Two estimands are defined: Estimand 1 evaluates effectiveness under a hypothetical scenario where control group participants would never receive nirsevimab, while Estimand 2 applies a treatment policy strategy, evaluating effectiveness regardless of subsequent nirsevimab receipt in controls.
• Setting:
  This study is conducted using routinely collected electronic health records from 2023 to 2025, reflecting the period of nirsevimab use in routine clinical practice. Pedianet is a national population database that contains anonymous patient-level data of paediatric population who received healthcare from family paediatricians (FPs) in Italy who were part of the PEDIANET network. The network links FPs distributed throughout several Italian regions designated by the Italian NHS, including Friuli-Venezia Giulia, Liguria, Lombardia, Piemonte, Veneto, Lazio, Marche, Toscana, Abruzzo, Campania, Sardegna, and Sicilia.
• Comparators:
  Each eligible infants exposed to nirsevimab will be matched with a non-exposed infants (comparator) at time 0. For the comparator group, “time 0” is defined as the date of receipt of nirsevimab for the matched exposed individual. This matching date is selected to mirror the temporal distribution of cohort entry in the exposed group, thereby minimising biases related to calendar time and seasonality (especially relevant in studies involving respiratory pathogens), as well as temporal changes in healthcare delivery or data capture. At time 0, comparator individuals are required to be alive, eligible, and not yet exposed to nirsevimab. Individuals in the comparator group who subsequently will receive nirsevimab during follow-up will be not contribute data to the study after the nirsevimab administration. To emulate a parallel-arm target trial, matching will be performed without replacement at each index date. Individuals can enter the study only once, at their first eligible index date.; ; Because infants in the unexposed group do not have a treatment administration date, a 1:1 matching procedure will be used to assign a comparable index date (time 0). For each infant receiving nirsevimab, one infant who did not receive nirsevimab will be selected and assigned the same index date, matched on age group at the time of nirsevimab administration (≤3.0 months, >3.0 to ≤6.0 months, and >6.0 months) and calendar week of administration. This matching procedure ensures alignment of follow-up time between exposure groups and accounts for age and calendar time. All subsequent assessments, such as the application of inclusion and exclusion criteria, outcome surveillance, and follow-up duration, are defined relative to this primary temporal anchor.
• Outcomes:
  RSV-LRTI hospitalization is the primary outcome of interest. This is a hard outcome that is of great interest to patients, clinicians, and policy decision makers.
• Data analysis plan:
  This study employs the target trial and the estimand frameworks to assess nirsevimab effectiveness in preventing RSV-LRTI hospitalization within six months of administration among infants ≤12 months compared to no immunization. For Estimand 1, the main estimand supporting decision making, we will estimate the relative risk (RR) under a hypothetical scenario in which participants in the control arm would not experience the intercurrent event of receiving nirsevimab. The status of the outcome of interest, RSV-LRTI hospitalisation, of subjects who experience this intercurrent event, will be considered missing. For the primary analysis, the RR will be estimated using an inverse probability of treatment weighted log-binomial regression model including group assignment as the main predictor and age. Sensitivity analyses will be performed to investigate the robustness of the results to assumptions made in the primary analysis.; ; For Estimand 2, a log-binomial regression model will be used as well, including all participants’ follow-up as randomised, regardless of receiving nirsevimab in the untreated group.; ; Supplementary analyses including diagnostic and descriptive assessments to support the main analysis will be conducted to contextualise data and results from the primary analysis.; ; An additional supplementary analysis will be produced whereby individuals in the control arm can contribute data multiple times to the control arm and also to the nirsevimab arm after reception of nirsevimab.