A single-center, randomized, open-label, two-arm study to evaluate the ovarian function inhibition of a monophasic combined oral contraceptive (COC) containing 15 mg estetrol (E4) and 3 mg drospirenone (DRSP) and a monophasic COC containing 20 mcg ethinylestradiol (E4)/3 mg drospirenone (Yaz®), administered orally once daily in a 24/4 day regimen for three consecutive 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) combined 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 progestogin 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). Yaz® has also been shown to improve
symptoms of premenstrual syndrome.

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 ovarian function inhibition, hypothalamic
pituitary ovarian (HPO) axis suppression during 3 treatment cycles and return
to fertility after 3 treatment cycles in comparison with the reference COC 20
mcg EE/3 mg DRSP.

Primary
- To evaluate the effects of the 15 mg E4/3 mg DRSP combination and the 20 mcg
EE/3 mg DRSP used as reference combination on ovarian function inhibition at
Treatment Cycle 1 and Treatment Cycle 3.

Secondary
- To evaluate levels of luteinizing hormone (LH), follicle-stimulating hormone
(FSH), estradiol (E2) and progesterone during Treatment Cycle 1, (Treatment
Cycle 2), and Treatment Cycle 3.
- To evaluate endometrial thickness.
- To evaluate return to fertility.
- To assess the safety and tolerability of the 15 mg E4/3 mg DRSP and the 20
mcg EE/ 3 mg DRSP combination.


Exploratory
- To evaluate the effect of 15 mg E4/3 mg DRSP and the 20 mcg EE/3 mg DRSP
combination on dysmenorrhea and breast tenderness/pain

This is a single-center, randomized, open-label, controlled, two-arm study in
healthy female subjects. Subjects will be stratified according to day of
ovulation in the Pre Treatment Cycle and BMI (* 30.0 kg/m2 and > 30.0 kg/m2) to
ensure an even distribution over treatment groups. Each subject will undergo a
screening visit, a Pre Treatment Cycle, followed by 3 treatment cycles, a
Post-Treatment Cycle, and a follow-up visit. In case of use of hormonal
contraception at least 1 wash-out cycle has to be performed before start of the
Pre-Treatment Cycle.

Subjects will visit the clinic regularly during the Pre-Treatment Cycle,
Treatment Cycle 1 and Treatment Cycle 3 and the Post-Treatment Cycle. One visit
is planned during Treatment Cycle 2.

Treatments will be administered once daily during 3 treatment cycles of 24 days
of active medication followed by 4 days of placebo.

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

After the subject passes all above mentioned tests, the subject will enter the
pre-reatment cycle. ln the pretreatment cycle vital signs, ovulation and
endometrial thickness will be analyzed. In addition the subject will score
their levels of dysmenorrhea and breast tenderness/pain.

Following the pre-treatment cycle subjects will be randomized to 1 of the 2
study arms. During cycle 1-3 vital signs, ovulation and endometrial thickness
measurements are repeated. In addition the subject will score their levels of
dysmenorrhea and breast tenderness/pain. At the end of cycle 3 subjects will
visit the cardiologist for an echocardiography and ECG.

After cycle 3 subjects will enter the post treatment cycle. ln the post
treatment cycle, ovulation and endometrial thickness will be analyzed. In
addition the subject will score their levels of dysmenorrhea and breast
tenderness/pain.

After the pre, during and follow-up cycles have been completed, the subject
will visit the clinic for a fìnal visit.

Subjects will be asked on a regular basrs for possible side effects throughout
the study. Cornpliance 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 contraceptive pills (the
pill) are: nausea, stomach pain, changes in weight, headache, including
migraines, mood changes, including depression, breast tenderness or pain, or
problems with your periods such as irregular periods, absence of periods.

Drawing blood may be painful or may cause some bruising.

Vaginal ultrasound examinations are usually painless. An ultrasound examination
does not pose any risk to you. Inserting the speculum and taking a smear of the
cervix can be somewhat discomfortable. You may have some light bleeding
afterwards.