Clinical trial NCT02280057: Trial With Metformin in Women With Polycystic Ovary Syndrome
Official title: Randomized, Cross-over Trial With Metformin in Women With Polycystic Ovary Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Polycystic Ovary Syndrome
Keywords: PCOS
metformin
obesity
randomized controlled trial
Lead sponsor: Herning Hospital
Sponsor class: OTHER
Collaborators: name: GEA A/S Denmark
First posted: 2014-10-31
Enrollment: 56
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The investigators wanted to elucidate the effects of metformin in Polycystic Ovary Syndrome (PCOS) by performing a randomized, double-blinded, placebo-controlled cross-over study.

Detailed description: Eligible women who gave written informed consent were assigned to 6 months of treatment with either 850 mg of metformin or placebo twice daily, followed by a wash-out period of 3 months before cross-over to the alternate treatment for another 6 months. Randomization defining treatment sequence was done at inclusion by random number tables. The appearance of the tablets was identical, and patients and investigators were blinded to treatment allocation. The randomization code was stored in a closed envelope until all participants had finished the treatment. Participants were seen by one of the investigators before inclusion and every second month during treatment periods, always in the morning after an overnight fast of at least 8 h. They were weighed wearing light clothing. Waist circumference was measured at the umbilical level and hip circumference at the trochanter region. Systolic and diastolic blood pressure was measured with a semiautomatic blood pressure monitor and a blood sample was drawn for immediate analysis without respect to bleeding periods. All participants registered their bleeding periods in a calendar during both study periods and the 3 months wash-out period. Calculation of sample size was based on the assumption that at least 50% of the women would experience at least 30% more menstrual periods on metformin than on placebo. Based on a power of 90 (b = 0.10) to detect a significant difference \[two-sided P-value of 0.05\], the minimum sampling size was calculated to 44 subjects.

We also assumed a 10% drop-out rate, and thus aimed at including 50 women. As drop-out rate quickly rose higher than expected, we decided to include 60 women. In the intention-to-treat analysis, the values of each participant after 6 months of metformin or placebo were compared with the baseline values. Linear regression analysis with the changes in testosterone and homeostasis model assessment (HOMA) index as dependent variables was performed to examine potential relations between the changes. The per protocol analysis included data from participants completing both study periods, i.e. the difference between the values of each participant after placebo and metformin, respectively, was calculated, and a significance test performed on the differences.

Eligibility criteria: Inclusion Criteria:

* testosterone value above the upper normal limit and
* oligo- or amenorrhea,

Exclusion Criteria:

* periclimacteric gonadotrophin values,
* hyperprolactinaemia,
* diabetes mellitus,
* impaired thyroid,
* renal or hepatic function,
* hormonal treatment,
* pregnancy,
* lactation or a wish for fertility treatment.

Primary outcomes:
measure: Testosterone (Levels of free testosterone)
timeFrame: six months
Secondary outcomes:
measure: Insulin sensitivity (measured homeostasis model assessment (HOMA) index)
timeFrame: Six months
Other outcomes:
measure: Body weight change
timeFrame: Six months
Locations:
city: Herning
country: Denmark
facility: Gynecology Dept. Herning Hospital
Study officials:
affiliation: Gyn Dept. Herning Hospital, Herning, Denmark
name: Finn F Lauszus, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial. Hum Reprod. 2007 Nov;22(11):2967-73. doi: 10.1093/humrep/dem271. Epub 2007 Aug 31.
citation: Trolle B, Lauszus FF, Frystyk J, Flyvbjerg A. Adiponectin levels in women with polycystic ovary syndrome: impact of metformin treatment in a randomized controlled study. Fertil Steril. 2010 Nov;94(6):2234-8. doi: 10.1016/j.fertnstert.2010.01.057. Epub 2010 Mar 2.
citation: Greibe E, Trolle B, Bor MV, Lauszus FF, Nexo E. Metformin lowers serum cobalamin without changing other markers of cobalamin status: a study on women with polycystic ovary syndrome. Nutrients. 2013 Jul 5;5(7):2475-82. doi: 10.3390/nu5072475.
citation: Madsen HN, Lauszus FF, Trolle B, Ingerslev HJ, Torring N. Impact of metformin on anti-Mullerian hormone in women with polycystic ovary syndrome: a secondary analysis of a randomized controlled trial. Acta Obstet Gynecol Scand. 2015 May;94(5):547-51. doi: 10.1111/aogs.12605. Epub 2015 Mar 4.