Multi-center, open-label, randomized study to assess the safety and contraceptive efficacy of two doses (in vitro 12 µg/24 h and 16 µg/24 h) of the ultra low dose levonorgestrel contraceptive intrauterine systems (LCS) for a maximum of 3 years in women 18 to 35 years of age with an extension of the LCS16 treatment arm up to five years

The experimental preparations of the ultra low dose levonorgestrel
(LNG)contraceptive systems (LCSs) in this study are intrauterine systems (IUSs)
initially releasing in vitro 12 and 16 µg of LNG per day. The study product is
similar to the MIRENA IUS (a product that has been on the market for many years
) initially releasing 20 µg of LNG per day (in vitro). In the experimental LCSs
the drug reservoir is mounted on a smaller T-shape frame with diameters of 28
mm horizontal width and 30 mm vertical length and insertion tube diameter of
3,80 mm, while MIRENA's diameters are 32 x 32 mm and 4,75 mm, respectively.
Therefore, the aim of this study is to search for a dose for a new
contraceptive IUS which provides reliable contraception for 3 years (with an
extension of the LCS16 treatment arm up to five years), but has a lower rate of
progestin-related systemic side-effects and easier and less inconvenient
insertion when compared to Mirena.

The objective of this study is to assess the safety, efficacy and
pharmacokinetics of 2 doses of LNG, delivered locally by a new intrauterine
contraceptive system suitable for use by women 18 to 35 years of age during 3
years and with an extension of the LCS16 treatment arm up to 5 years.

This study is a multi-center, open, randomized, safety and efficacy phase III
study. The number of pregnancies will be recorded and pregnancy rate will be
calculated as the primary variable of this study. Transvaginal ultrasounds will
be performed at each of the 10 scheduled visits. The ultrasound will be
performed to ensure subject's safety including correct placement of the LCS.
Bleeding pattern and information on dysmenorrhea will be collected on
subject-kept diaries. LCS insertion and removal ease and pain will be evaluated
by the subject (pain) and the investigator (ease). Serum levels of LNG and sex
hormone binding globulin (SHBG) will be monitored by means of sparse blood
sampling and will be evaluated using a population pharmacokinetic approach (one
sample per subject taken at different time-points during the 3 years of the
study). All adverse events will be recorded as reported voluntarily by the
subject or elicited. Progestin related adverse event will be collected from the
adverse event data and reported separately. Adverse events specific to the use
of intrauterine systems will receive special attention. General safety will be
assured prior to entry and monitored during the study. Pregnancy testing will
be done at entry, termination of trial and as necessary during the study. After
one year from the cessation of treatment, if the subject discontinued
prematurely for a wish to get pregnant, the return to fertility will be
assessed by a questionnaire.

Two different in vitro doses (daily release rates) of intrauterine LNG,
designated as LCS, are studied in this study: Arm 1: 12 µg/day and arm 2: 16 µg/
day. In the extension study only women can participate, who are in the LCS16
treatment arm yet.

Contraceptive failure is possible with all available contraceptive methods.

Expulsion of the LCS is possible in this study. Expulsion, especially when
unnoticed, may be associated with an unwanted pregnancy.

Pelvic infection is possible in this study. Such infection is mainly associated
with behavioral factors such as multiplicity of sexual partners.

Ectopic pregnancy is possible in this study.

Uterine perforation occurs in 1/1000 of insertions and at the same rate for all
intrauterine devices and hormone releasing systems including Mirena.

LNG-releasing IUSs are associated with scanty bleeding and spotting especially
during the first 3 months of use whether used for contraception or endometrial
protection. The new LCS is expected to show a similar bleeding profile.

Other side-effects are possible in this study. The typical progestin-related
side-effects are headache, nausea, bloating, edema, skin effects, breast pain
and tension and weight gain. However, these side-effects are expected to occur
less frequently with the new LCS compared to Mirena.