Clinical trial NCT01588873: Contraceptive Pill and Hormonal Vaginal Ring in Women With Polycystic Ovary Syndrome
Official title: 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).
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Adverse Effect of Oral Contraceptives, Sequela
Keywords: Oral contraceptive pill
Hormonal contraceptive ring
Polycystic ovary syndrome
Lead sponsor: University of Oulu
Sponsor class: OTHER
First posted: 2012-05-01
Enrollment: 42
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main aims of this study are:

* to investigate and compare the effects of long lasting use (59 weeks) of vaginal and oral contraceptives on androgen secretion, insulin and glucose metabolism, lipid profile, and serum levels of SHBG and hs-CRP in women with PCOS.
* to compare the metabolic effects of oral and vaginal combined contraceptives and to find out whether oral or transvaginal contraceptive can be recommended to a particular group of women, for example in women with increased metabolic risks.
* to clarify whether the unfavourable effects of combined contraceptives diminish with time (after use of one year).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* women aged between 18 to 40 years
* diagnosed PCOS (Rotterdam criteria)
* healthy, no medications
* no use of hormonal contraceptives or wash-out period of at least two months
* no contraindications to hormonal contraception

Exclusion Criteria:

* regular smoking
* excessive alcohol use
* pregnancy or breastfeeding
* oversensitivity to active ingredients
* migraine with focal aura
* severe or multiple risk factors to thrombosis
* diagnosed or suspected cancer
* diagnosed or suspected estrogen-dependent tumor
* acute or chronic hepatocellular disease -related abnormal liver function
* hepatic adenomas or carcinomas
* undiagnosed abnormal vaginal bleeding

Primary outcomes:
measure: Change in Matsuda index during the oral contraceptive pill (E-E-desogestrel)/vaginal ring (E-E -ethonogestrel)
timeFrame: Change from baseline in Matsuda index at 59 weeks of treament
Secondary outcomes:
measure: Change in high sensitive C-reactive protein (mg/l) during the oral contraceptive pill (E-E-desogestrel)/vaginal ring (E-E -ethonogestrel)
timeFrame: Change from baseline in serum CRP concentrations at 59 weeks of treament
measure: Change in Free Androgen Index during the oral contraceptive pill (E-E-desogestrel)/vaginal ring (E-E -ethonogestrel)
timeFrame: Change from baseline in Free Androgen Index at 59 weeks of treament
Other outcomes:
Locations:
city: Oulu
country: Finland
facility: Department of Obstetrics and Gynaecology, University Hospital of Oulu
Study officials:
affiliation: University of Oulu
name: Laure C Morin-Papunen
role: PRINCIPAL_INVESTIGATOR
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