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 oestrogen only produced during pregnancy by the foetal liver.
When combined with the progestin DRSP, ovulation is inhibited. The E4/DRSP combination
may have less impact on hepatic and haemostasis parameters in comparison to combinations
of ethinyl estradiol (EE) and levonorgestrel (LNG) or EE and DRSP. Yet, it is unknown
whether this regimen has an impact on the cardiovascular risk associated with the use of
hormonal contraceptives.
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 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 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.
Population:
Approximately 101,000 study participants (50,500 E4/DRSP and 50,500 EE/LNG new users)
will be recruited via a network of COC-prescribing health care professionals in Europe,
the USA, and Brazil. 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.
Data sources:
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).
Study size:
The study is sufficiently powered to show non-inferiority of E4/DRSP compared to EE/LNG
assuming that the VTE risk among E4/DRSP users is not higher than among EE/LNG users. For
this purpose, a total of 101,000 women (50,500 E4/DRSP users and 50,500 EE/LNG users)
will be recruited and followed up taking into account treatment adherence, treatment
stopping/switching, and lost to follow-up (LTFU)/dropout.
Data analysis:
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.