A randomized, double-blind, placebo-controlled, parallel, single center study to investigate the pharmacokinetics, safety, and tolerability of Estetrol (E4) in combination with Drospirenone (DSRP) after single and multiple dosing in healthy women.

The combined oral contraceptive pill (COCP), often referred to as the birth
control pill or just *the pill*, is a birth control method that includes a
combination of two types of hormones: an estrogen (usually ethinyl estradiol)
and a progestogen. When taken orally every day, the pill inhibits fertility.
Estelle® is being developed by Estetra SPRL as a new COCP containing a new
estrogen called *estetrol* (also called *E4*) and an existing progestogen
called *drospirenone* (DRSP). E4 is a natural estrogen only produced by the
fetal liver during human pregnancy. DRSP is the progestogen used in some
marketed COCPs (such as Yaz®). The combination of E4 and DSRP is expected to
have the same efficacy as current COCPs but with fewer side effects often seen
with COCPs containing ethinyl estradiol. Estelle® is not registered as a drug
but has been given to humans before.

The purpose of the study is to investigate how quickly and to what extent
single and multiple doses of Estelle® are absorbed by and eliminated from the
body (this is called pharmacokinetics). It will also be investigated how safe
Estelle® is and how well Estelle® is tolerated, amongst others by looking at
the effects on the electrical activity of the heart at doses that are higher
than the expected optimal dose for contraception, being 15 milligrams (mg) E4
and 3 mg DRSP (see next Chapter *How much of the study compound will I
receive?*). Amongst others, it will be evaluated if there is a prolongation of
the so-called QT interval; the QT interval is a variable measured by a heart
trace. When the QT interval is prolonged, repolarization is delayed. This means
that cardiac cells need more time to prepare for the next beat. When a new
heartbeat is about to start and not all cardiac cells are prepared for that,
arrhythmias (heart rhythm problems) may develop. Safety and tolerability will
further be investigated by looking at blood parameters and by making an
echocardiogram.
This study will be performed in a maximum of 56 healthy female volunteers
divided over 4 groups of 14 volunteers.

Before the study the volunteers will undergo a pre-study screening within 49
days before the first day of administration of the study compound (Day 1)
during which they will be subjected to a number of medical examinations.
Similar examinations will be performed after the study at the post-study
screening which will be conducted within 36 to 40 days (Day 37-41) after the
first day of administration of the study compound. The appointment for the post
study screening will be made with the volunteers during the study.

After the initial pre-study screening, they will undergo a second pre-study
screening. During this second pre-study screening, a cervical smear test and a
bimanual examination of the uterus will be performed in the Martini Hospital in
Groningen. The cervical smear test will not be needed when it has been done
within 1 year prior to this screening, when PRA has the permission to request
the results from the general practitioner and when the result of the test is
available and normal.

The actual study will consist of 2 periods as follows:
* Period 1 starts on Day -2 (2 days before first administration of the study
compound) and ends on Day 14:
o On Day -2, they are expected at 8:30 hours in the morning in the clinical
research center in Groningen. They will leave in the morning of Day 3; thus
they will stay for 5 days (4 nights).
o On Days 4, 5, 6, 7 and 8, they are expected for a short visit at 8:30 hours
in the morning in the clinical research center in Groningen; they will leave
the clinical research center within a few hours. Subsequently they are not
expected anymore in the clinical research center up to Day -14.
* Period 2 starts on Day 15 and ends on Day 35:
o On Days 15, 17, 19, 21, 23 and 25, the volunteers are expected for a short
visit at 8:30 hours in the morning in the clinical research center in
Groningen; they will leave the clinical research center at the beginning of the
afternoon.
o On Day 26, they are expected at 14:00 hours in the afternoon in the clinical
research center in Groningen. They will leave in the morning of Day 29; thus
they will stay for 4 days (3 nights).
o On Days 30, 31, 32, 33, 34 and 35, the volunteers are expected for a short
visit at 8:30 hours in the morning in the clinical research center in
Groningen; they will leave the clinical research center within a few hours.

Group Dose Level E4 (mg) Dose Level DRSP (mg) Dosage
Group 1 15 3
therapeutic E4/DRSP dose level
Group 2 30 6 2
times therapeutic E4/DRSP dose level
Group 3 60 12 4
times therapeutic E4/DRSP dose level (supratherapeutic dose)
Group 4 TBD TBD
TBD

Pain, minor bleeding, bruising, possibly an infection due too blood sampling.