Trial Information

The Effects of Contraceptive Pill and Hormonal Vaginal Ring on Hormonal, Inflammatory and Metabolic Parameters in Women of Reproductive Age With Polycystic Ovary Syndrome (PCOS).

The study population consists of women of reproductive age with PCOS, no wish of pregnancy
and no other contraindications to hormonal contraceptives.

The volunteer subjects will be recruited from hospital's patient files with PCOS (IC
diagnosis E.28.2).

Methods Sample size Our previous study comparing the metabolic effects of the same
preparations (Mercilon and Nuvaring) in young healthy women shown an significant decrease of
1.65 (SD 1.68)in the Matsuda index at 9 weeks of treatment with oral contraceptive pill.
Power analysis indicated that 14 women would be needed in both groups to reveal a similar
significant decrease in the serum level of Matsuda index. To allow for drop-outs (estimated
to be as high as 20-30%), the planned sample size will be 21 in each group.

Medication Forty women will be randomised either to the pill (n=21) or ring (n=21) group.
The OC or contraceptive ring will be used in nine weeks periods. Every period will be
followed by a break of one week.

In the pill group the subjects start the pill during the first days of the follicular phase
of the cycle after the baseline examinations and continue nonstop for nine weeks, i.e. until
the third package has ran out. This is followed by one weeks' break. The ring is replaced
every three weeks and the treatment is continued nine weeks after which one week break
follows. In both groups the cycle will be repeated six times resulting in 59 weeks of
treatment.

The used preparations are: Vaginal ring, depotproduct: ethinylestradiol 2.7 mg (0,015
mg/day) and etonogestrel 11.7 mg (0,120 mg/day)and the contraceptive pill, ethinylestradiol
tabl 20 µg, desogestrel 150 µg.

Ultrasonography An ultrasonography of the ovaries will be performed at baseline to support
the diagnosis of PCOS and exclude any androgen releasing tumors.

Blood samples Blood samples for hormonal and metabolic assessments will be taken at every
appointment.

Oral glucose tolerance test (OGTT) The glucose metabolism and tolerance are measured with an
oral glucose tolerance test, where the subjects take a dose of 75 grams of glucose mixed in
300ml of water after ten hours fasting. The blood samples are taken before the test and 30,
60 and 120 minutes after the glucose intake.

The schedule A wash-out period of at least 2 months after the use of any previous hormonal
contraceptives will be required. At baseline all examinations are performed at the 1st to
5th day of the menstruation cycle before beginning contraception.

The second appointment will occur during the 9th pill/ring week, the third at the 29th
week, the fourth at the 59th week and the last appointment one month after stopping
contraception. Blood samples are taken and blood pressure is measured at every appointment,
OGTT will be performed at every appointment except at the 29th week.

Serum analyses All blood samples will be collected in the morning between 07 and 10 after an
overnight fast and during the follicular phase (cycle days 1-4) or at any time in cases of
amenorrhea. All screening analyses will be analysed at the local hospital.

Seven test-tubes whole blood are collected from each patient. Six tubes are centrifuged
within 30 minutes, and serum is filled in eight (8) tubes with at least 2 ml of serum in
each, and immediately frozen at -70 º C. In addition, the plasma from one tube will frozen
at -70 º C in at least 2 tubes with at least 2ml plasma in each. Every tube is marked by
randomisation number, initials, date of birth and time.

Fasting plasma glucose and HbA1c will be analysed at once at every appointment at the local
hospital.

Planned analyses Hormonal, metabolic and inflammatory parameters. Ethical questions and
possible harmful effects Participating in the research is completely voluntary. When taking
the blood samples, the risks are practically restricted to the problems caused by the stitch
of the needle.

The possible adverse effects of the used contraceptives are observed at every appointment.
Problems are reported to FIMEA (Finnish Medical Association) and to the local ethical
committee, if necessary.

A continuous dosing is used in this study, which is not routine treatment. Uninterrupted
dosing of contraceptive pills has been used in several studies and no differences in the
contraceptive effect compared to routine dosing have been reported. Instead, the
menstruation comes less frequently which is user-friendly. Continuous dosing may cause
slightly more swelling and extra leakage.

After the study the treatment of the subjects continues following standard practice.

All information required will be kept locked in cupboards, and disposed ten years after the
study has ended. Information on computer requires username and password.

Analysing the results and their significance Blood samples are analyzed in Oulu University
Hospital laboratory of Clinical Chemistry, which fulfills international quality criteria.
The results are analyzed using SPSS-program. During the research Oulu University
statistics-professional will be consulted for help in the statistical analyses.

Significance of the study:

This study will allow to clarify whether oral or transvaginal contraceptive can be
recommended to a particular group of women, for example in women with increased metabolic
risks. It will also clarify whether the unfavourable effects of combined contraceptives
decrease after long term use.

Concealment and disposing the register The information and study data will be kept on
computer requiring a username and password. All written information will be kept in a room
in locked cupboards. The register will be disposed following ethical committee's
instructions no later than the end of 2027.

Schedule The study will begin in spring 2012 and is estimated to continue until December
2018.

Funding The study will be funded by the Sigrid Juselius organization and from the Kevo-fund
of Department of Obstetrics and Gynaecology of Oulu University Hospital.

Changes in the plan Every possible changes in the study design will be reported to the local
Ethical Committee.