International Active Surveillance Study: Native Estrogen Estetrol (E4) Safety Study (INAS-NEES)

Study type

• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  (G03AA18) drospirenone and estetrol

  drospirenone and estetrol
• Medical condition to be studied:
  Atrial thrombosis

  Deep vein thrombosis

  Pulmonary embolism

  Venous thrombosis

  Myocardial infarction

  Cerebrovascular accident

  Unintended pregnancy

  Congenital anomaly

Population studied

• Age groups:
  Adolescents (12 to < 18 years)

  Adults (18 to < 46 years)

  Adults (46 to < 65 years)
• Estimated number of subjects:
  101000

Study design details

• Main study objective:
  The primary objective of the study is to characterize and compare the risks of E4/DRSP with EE/LNG, in a study population that is representative of the actual users of these preparations.
• Outcomes:
  The main clinical outcome of interest is venous thromboembolism (VTE), i.e. deep venous thrombosis (DVT) of the lower extremities and pulmonary embolism (PE). Secondary objectives include measuring the occurrence of unintended pregnancy, assessing the risk of arterial thromboembolism (ATE), describing the drug utilization pattern, describing the baseline risk profile for VTE and ATE, and investigating outcomes associated with foetal exposure to E4/DRSP.
• Data analysis plan:
  The final analyses will include both an “as-treated” (AT) and an “intention-to-treat” (ITT) analysis. All eligible women will be assigned to the ITT and AT population at baseline. Only women with follow-up information will be considered for longitudinal analysis. Women who never started their prescribed baseline medication will be considered in the ITT analysis but excluded from the AT analysis. Population characteristics, e.g. socio-economic factors, parameters of reproductive, contraceptive history, and medical history, will be summarized descriptively and used to estimate the probability of treatment differences. Inverse probability of treatment weighting combined with time-to-event analysis of VTE will be carried out based on the extended Cox model to calculate hazard ratios (HR) with 95% confidence intervals. The null hypothesis to be tested is HR of VTE ≥1.5 (i.e. the VTE HR for E4/DRSP vs. EE/LNG is higher than or equal to 1.5). The alternative hypothesis is HR of VTE<1.5.