International Active Surveillance Study: Safety of Estrogen Estetrol (E4) Contraceptive Study (INAS-SEECS)

Rationale and background: The combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP) (E4/DRSP) is a novel oral contraceptive containing a fixed dose of E4 (14.2 mg) and DRSP (3 mg). E4 is a natural estrogen only produced during pregnancy by the fetal liver. When combined with the progestin DRSP, ovarian activity is suppressed, and there is less impact on hepatic parameters and hemostasis in comparison to combinations of ethinyl estradiol (EE) and levonorgestrel (LNG) or EE and DRSP. The E4/DRSP combination has now received marketing authorization in multiple locations, including the United States of America (USA). The proposed study will address post-market requirements for E4/DRSP under section 505(o) in response to the Food and Drug Administration (FDA) request.

Two co-primary comparisons will be conducted regarding the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE): new users of E4/DRSP vs. non-DRSP COCs (comprising LNG, norethisterone/norethindrone acetate [NETA] and norgestimate [NGM] in combination with EE) and E4/DRSP vs. other DRSP-containing products (EE/DRSP) among women of reproductive age using COCs primarily for contraceptive reasons. An adequate number of obese women in the US population will be included for analysis. The study will be adequately powered to rule out a 2.0-fold increase in the risk of VTE for both the E4/DRSP vs. non-DRSP COCs, and the E4/DRSP vs. EE/DRSP COCs analyses.

Research question and objectives: The primary objective of the study is to characterize and compare the risks of E4/DRSP with EE/DRSP and E4/DRSP with a pooled cohort of users of EE/LNG, EE/NETA, and EE/NGM combinations (non-DRSP-containing COCs) in a study population of actual users of these preparations under routine clinical practice. The main clinical outcome of interest is VTE. Secondary objectives include measuring the occurrence of unintended pregnancy, assessing the risk of ATE, deep venous thrombosis (DVT) of the lower extremities, and pulmonary embolism (PE), describing the drug utilization pattern, and describing the baseline risk for VTE and ATE.

Study design: The INAS-SEECS study is a comparative, prospective, active surveillance study that follows three cohorts. The cohorts consist of new users (starters and restarters ) of hormonal contraceptives and focus on two co-primary comparisons: E4/DRSP versus EE/DRSP and E4/DRSP versus non-DRSP COCs. The study uses a non-interventional approach to provide comprehensive information on these treatments in a routine clinical practice setting. Study participants will be enrolled via an international network of COC-prescribing health care professionals (HCPs) and followed up for 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/or relevant source documents. The classification of outcomes of interest into 'confirmed' and 'not confirmed' will be verified by blinded independent adjudication.

Population: Approximately 68,100 study participants (22,700 E4/DRSP, 22,700 EE/DRSP, and 22,700 EE/LNG, EE/NETA, and EE/NGM users) will be recruited via a network of COC-prescribing HCPs in the USA. All new users (starters and restarters with at least two months break) prescribed E4/DRSP, EE/DRSP, EE/LNG, EE/NETA, or EE/NGM who are willing to participate may be eligible for enrollment in the study. The distribution of body mass index (BMI) categories will be monitored during the recruitment period, and if necessary, a quota will be introduced. However, women who have given birth six weeks before treatment starts will be excluded from the study. Participants with a prior cancer diagnosis (less than six months) and a prior VTE (Medical history of VTE at study entry) and those using anticoagulants will be excluded from the primary analysis of VTE. However, they will be considered in the sensitivity analyses.