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

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Evaluation of patient-reported outcomes
• Data collection methods:
  Primary data collection

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Name of medicine:
  DROVELIS

  LYDISILKA
• Study drug International non-proprietary name (INN) or common name:
  DROSPIRENONE

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

  drospirenone and estetrol

  (G03AA18) drospirenone and estetrol

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

  Deep vein thrombosis

  Pulmonary embolism

  Unintended pregnancy

  Congenital anomaly

  Pulmonary embolism

Population studied

• Short description of the study population:
  Approximately 101,000 study participants (50,500 estetrol (E4)/drospirenone (DRSP) and 50,500 ethinyl estradiol (EE)/levonorgestrel (LNG) new users) will be recruited via a network of COC-prescribing health care professionals in Europe and the USA. ; All new users (starters and restarters) prescribed E4/DRSP or EE/LNG who are willing to participate may be eligible for enrolment in the study.
• Age groups:
  • Paediatric Population (< 18 years)

    • Adolescents (12 to < 18 years)
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)
• Special population of interest:
  Women of childbearing potential using contraception
• Estimated number of subjects:
  101000

Study design details

• Study design:
  Multinational, comparative, prospective, active surveillance study that follows two cohorts. ; The cohorts consist of new users (starters and restarters) of two different groups of hormonal contraceptives: E4/DRSP and EE/LNG. ; The study is taking a non-interventional approach.
• 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.
• Setting:
  Study participants will be enrolled via an international network of COC-prescribing health care professionals (HCPs) and then followed up for one to two years. ; All outcomes of interest will be captured by direct contact with the study participants. ; Reported outcomes of interest will be validated via attending physicians and relevant source documents. ; The classification of outcomes of interest into ‘confirmed’ and ‘not confirmed’ will be verified by blinded independent adjudication. Approximately 101,000 study participants (50,500 E4/DRSP and 50,500 EE/LNG new users and re-starters) will be recruited via a network of COC-prescribing health care professionals in Europe and the USA. ; All new users (starters and restarters) prescribed E4/DRSP or EE/LNG who are willing to participate may be eligible for enrolment in the study. ; The variable to determine the primary endpoint is the occurrence of a new VTE (DVT of the lower extremities and PE) during follow-up, which will be compared between E4/DRSP and EE/LNG users. ; Variables to determine the secondary endpoints include the occurrence of unintended pregnancies, ATE, and outcomes associated with foetal exposure to E4/DRSP.; Variables to characterize the baseline risk profile of users are baseline population characteristics,; socio-economic factors, parameters of reproductive, contraceptive, and medical history, and concomitant medication. ; This is a field study that entails exposure to COCs and the occurrence of clinical outcomes of interest by completing questionnaires at baseline (study entry) and follow-up (at 6-, 12-, 18-, and 24-months post-baseline), in addition to potential confounding factors and potential effect modifiers. ; Medical confirmation of the occurrence of a clinical outcome of interest will be sought from the attending HCP and/or study participant (e.g., diagnostic report, discharge letter).
• 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 fetal 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.