A single center, randomized, open-label, controlled, three-arm study to evaluate the effect of a new combined oral contraceptive (COC) containing 15 mg Estetrol (E4) and 3 mg Drospirenone (DRSP) and of two reference COCs containing either 30 mcg Ethinylestradiol (EE) and 150 mcg Levonorgestrel (LNG) or 20 mcg EE and 3 mg DRSP on endocrine function, metabolic control and hemostasis during 6 treatment cycles

Combined hormonal contraception refers to birth control methods that act on the
endocrine system to inhibit ovulation. Traditionally the combined oral
contraceptives (COCs) contain 2 steroids: one with progestogenic and the other
with estrogenic effects. The function of the progestin is to inhibit ovulation
by a central feedback mechanism resulting in decreased luteinizing hormone (LH)
secretion by the pituitary gland. The estrogen component also contributes to
contraceptive activity by inhibiting the secretion of follicle stimulating
hormone (FSH) but the major function of estrogens included into the
contraceptive pill is to provide stability to the endometrium and consequently
to provide acceptable cycle control and bleeding pattern. Additionally, it
prevents estrogen deficiency (manifested as vaginal atrophy and decreased bone
formation). COCs have been shown to be highly effective in terms of
contraception. They are widely used in the industrialized world.

Estetra SPRL is developing a new COC containing a synthetic form of a natural
estrogen called estetrol (E4) in association with drospirenone (DRSP) as
progestin.

E4 is only produced by the human fetal liver. It reaches the maternal
circulation through the placenta. E4 has been isolated in maternal urine as
early as Week 9 of gestation. At pregnancy term, the hormone is found at
relatively high concentration (about 1 ng/mL) in maternal plasma and at over 10
times higher in fetal plasma

DRSP is an analogue of the aldosterone antagonist, spironolactone, with a
pharmacological profile more closely related to that of natural progesterone.
It is devoid of androgenic, estrogenic, glucocorticoid, and anti-glucocorticoid
activity, but possesses potent anti-mineralocorticoid and anti-androgenic
properties. DRSP is a progestogen with established use in COCs in combination
with ethinylestradiol (EE) (Yasmin®, Yaz®). The use of EE/DRSP combined
tablets, in addition to its contraceptive efficacy, may minimize
estrogen-inducing water and sodium retention, and reduce side effects such as
breast tension, weight gain and acne, which can occur with conventional COCs
combining EE and levonorgestrel (LNG).

A COC containing 15 mg E4 and 3 mg DRSP administered for 24 days followed by 4
placebo tablets, is being evaluated for further development. This study will
investigate the effect of this COC on endocrine function, metabolic control and
hemostasis during 6 treatment cycles, in comparison with two reference COCs

Primary:
To evaluate the effects of 15 mg E4/3 mg DRSP, of 30 mcg EE/150 mcg LNG, and of
20 mcg EE/3 mg DRSP on hemostasis, endocrine function and lipid and
carbohydrate metabolism parameters during 6 treatment cycles.

Secondary:
To assess the safety and tolerability of 15 mg E4/3 mg DRSP, of 30 mcg EE/150
mcg LNG, and of 20 mcg EE/3 mg DRSP during 6 treatment cycles

This is a single center, randomized, open-label, controlled, three-arm study in
healthy adult female subjects. A total of 100 (40 in the investigational group
and 30 per reference group) eligible subjects will be randomized. Subjects will
be stratified by previous hormonal contraception use (2 cycles or more than 2
cycles without hormonal contraceptive use before start study treatment) and by
age (*35 years or >35 years of age) to ensure an even distribution over
treatment groups. Subjects using hormonal contraception will have a washout
period of 1 cycle. Thereafter, each subject will undergo 1 pretreatment cycle,
followed by 6 treatment cycles. There will be 5 visits to the clinical site for
screening (Visit 1) and assessments (Visits 2-5).

The study will start with a screening visit. During the screening visit
standard medical assessments including safety laboratory tests (blood draw), a
physical examination, ECG and a vital signs measurement will be performed. In
addition a standard gynecological examination will be performed including a
cervical smear (if not done in the past 18 months)

After the subject passes all above mentioned tests, the subject will enter the
pre-treatment cycle. In the pre-treatment cycle vital signs, endocrine
parameters, lipid parameters, hemostasis parameters, glucose metabolism (OGTT),
liver proteins and a cardiac profile will be analyzed. During the pre-treatment
cycle the subject will also visit a cardiologist for an echocardiography.

Subjects will be randomized to 1 of the 3 study arms. During cycle 3 and cycle
6 the analysis of the endocrine parameters, lipid parameters, hemostasis
parameters, glucose metabolism, liver proteins and a cardiac profile will be
repeated. In addition a visit to the cardiologist for an echocardiography is
scheduled (cycle 6). During visit 2, 3 and 4 the subjects will complete a
Menstrual Distress Questionnaire.

After cycle 6 subjects will visit the site for a final visit.

Subjects will be asked on a regular basis for possible side effects throughout
the study. Compliance of the study medication will be monitored by means of a
paper diary. This diary will be completed by the subjects each day.

The most commonly observed side effects of combined oral contraceptives (the
pill) are: nausea, stomach pain, changes in weight, headache, including
migraines, mood changes, including depression, breast tenderness or pain, or
problems with the subjects periods such as irregular periods or absence of
periods. A complete list of possible side effects of the different types of
study medication can be found in Appendix 3 of the ICF.

Blood collection might be painful or the subject may become temporarily dizzy.
Furthermore, the subject may experience complaints like a puncture site bruise,
blot clot in the punctured vessel (rarely), puncture site infections (rarely),
mechanical nerve damage (very rarely) or anemia.