Prospective controlled cohort study on the safety of a monophasic oral contraceptive containing nomegestrol acetate (2.5mg) and 17ß-estradiol (1.5mg) (PRO-E2)

Study type

• Study topic:
  Disease /health condition

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

  Drug utilisation

  Effectiveness study (incl. comparative)
• Data collection methods:
  Primary data collection

Non-interventional study

• Non-interventional study design:
  Cohort

  Other
• Non-interventional study design, other:
  Intensive monitoring schemes, multinational controlled prospective active surveillance study

Study drug and medical condition

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

  NOMEGESTROL ACETATE
• Medical condition to be studied:
  Deep vein thrombosis

  Pulmonary embolism

  Arterial thrombosis

  Depression

  Cholelithiasis

  Inflammatory bowel disease

  Weight fluctuation

  Hepatobiliary disease

  Acne

Population studied

• Short description of the study population:
  All starters and restarters of NOMAC-E2 or COCLNG who are willing to participate in the study are eligible for enrollment into the study.; ; Subjects were considered for enrollment in the PRO-E2 Study after the participating physician and the woman had determined that NOMAC-E2 or COCLNG use was appropriate. There were no specific medical inclusion/exclusion criteria and no age restrictions (to fulfill the pediatric investigation plan (PIP) requirement in the EU). However, women who 1) were pregnant within 3 months before treatment initiation or 2) had a history of cancer/chemotherapy or an increased genetic risk for VTE at baseline were excluded from the main analysis of VTE.
• Age groups:
  Adolescents (12 to < 18 years)

  Adults (18 to < 46 years)

  Adults (46 to < 65 years)
• Special population of interest:
  Women of childbearing potential not using contraception

  Women of childbearing potential using contraception
• Estimated number of subjects:
  101000

Study design details

• Main study objective:
  To characterise and compare the risks of short- and long-term use of NOMAC-E2 with levonorgestrel-containing combined oral contraceptives (COC-LNG) in a study population that is representative of the actual users of the individual preparations. This includes an estimate of the absolute risk of rare serious adverse outcomes (e.g. venous thromboembolism, arterial thromboembolism).
• Outcomes:
  The main clinical outcomes of interest for short- and long-term follow-up are venous thromboembolisms (VTEs), specifically: 1. Deep Venous Thrombosis of the lower extremities 2. Pulmonary Embolism, For NOMAC-E2 and COC-LNG users, describe, measure and compare: 1. All VTE 2. Arterial thromboembolism incidence rate (IR) 3. Depressive disorders IR 4. Cholelithiasis IR 5. Inflammatory Bowel Disease IR 6. Effect on short-/long-term fertility 7. Drug utilization patterns and baseline risks for clinical outcomes 8. Pregnancy outcomes 9. Weight change 10. Hepatobiliary disorders 11. Acne
• Data analysis plan:
  Sample size considerations are based on the expected VTE incidence of COC-LNG (10 VTE per 10,000 woman years as requested by CHMP). It is expected that NOMAC-E2 is associated with a VTE risk that is not higher than with COC-LNG. A non-inferiority approach will be used to test hypotheses. Crude and adjusted hazard ratios will be calculated, with stratification of women into user categories (first-ever user, re-starter). The final decision on confounding variables will be made by the Safety Monitoring and Advisory Council. Similar analyses will be performed for all VTE, arterial thromboembolism (which includes acute myocardial infarction and cerebrovascular accidents), other secondary variables and other serious adverse events. A detailed analysis plan will be developed by the Principal Investigator during the first year after study start. The final analysis plan will be approved by the Safety and Monitoring Advisory Council before the first interim analysis of follow-up data.