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Polycystic Ovary SyndromePhase 3NCT00994812

The Effects of Metformin on Pregnancy and Miscarriage Rates in Polycystic Ovary Syndrome (PCOS)

A Phase 3 study testing metformin in people with Polycystic Ovary Syndrome and Miscarriage, run by University of Oulu at 5 sites in Finland.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to determine whether metformin may improve pregnancy rates, and decrease miscarriage rates and complications of pregnancy, such as toxemia and gestational diabetes, in women with polycystic ovary syndrome (PCOS). Read more about this study

Who is it for?
Ages 18 to 40 years, women only
What is being tested?
metformin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
326 participants
Where
5 sitesFinland
Study dates
Aug 2002to Dec 2009
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 40 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • age < 40 years at entry
  • BMI > 19 kg/m2
  • Infertility lasting > 1 year
  • Criteria for PCOS are as defined by ESHRE/ASRM: at least two of the following findings:
  • polycystic ovaries shown by vaginal ultrasonography (more than 12 subcapsular follicles of 3-8 mm diameter in one plane of the ovary)
  • oligomenorrhea or amenorrhea
  • clinical manifestations of hyperandrogenism such as a hirsutism score of > 7 according to Ferriman and Gallwey (Ferriman \& Gallwey 1961)and/or an elevated serum testosterone level (> 2.7 nmol/l).

Who cannot join

  • diabetic subjects
  • alcohol users
  • active liver disease (ALAT > +2 SD the upper normal value i.e.> 100IU/l)
  • hormonal drugs
  • past or present cardiac failure (NYHA I-IV)
  • liver or renal failure (S-Creatinine above the normal value ie.124 umol/l)
  • pregnancy or lactation
  • hypersensitivity to metformin

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

Finland5 sites

  • University Hospital Of Helsinki

    Helsinki

  • University Hospital of Kuopio

    Kuopio

  • University Hopsital of Oulu

    Oulu, 90029

  • University Hospital of Tampere

    Tampere

  • University Hospital of Turku

    Turku

Other trials in Finland

About this study

Official title: Effects of Metformin on Fertility and Pregnancy in Women With Polycystic Ovary Syndrome: a Randomized, Prospective, Placebo-controlled Multicenter Study

The purpose of this study is to determine whether metformin may improve pregnancy rates, and decrease miscarriage rates and complications of pregnancy, such as toxemia and gestational diabetes, in women with polycystic ovary syndrome (PCOS).

Read the detailed description

Women with PCOS represent about 5-10% of the general female population and one third of the women treated for infertility. Thus, the development of new therapies to improve the efficiency of ovulation induction treatments and the outcome of pregnancy, and to reduce the long-term risks of the syndrome would bring important health benefits.

The central role played by insulin resistance and hyperinsulinemia in PCOS - causing hyperandrogenism, premature follicular atresia, anovulation, oligo-amenorrhea and anovulatory infertility - has led to the use of insulin-lowering drugs for the treatment of this syndrome. The most studied agent is metformin, a biguanide antihyperglycemic drug used to treat Type 2 diabetes mellitus. It has been shown to improve significantly hyperinsulinemia and insulin resistance, to decrease androgen levels, and to improve menstrual pattern and, alone or in addition to clomiphene citrate, to induce ovulation and improve pregnancy rates in women with PCOS in some studies (1,2). Metformin may also decrease risks of early spontaneous miscarriage and gestational diabetes in PCOS (3-6). Two recent RCTs, however, have shown no beneficial effect of metformin compared to placebo as regards rates of pregnancy, miscarriage or life births in women with PCOS (7,8).

Our hypothesis is that metformin may improve pregnancy rates and decrease miscarriage occurrence and complications of pregnancy, such as toxemia and gestational diabetes, in women with PCOS. This multicenter randomized placebo-controlled study is conducted in all five University Hospitals of Finland (Oulu, Kuopio, Helsinki, Tampere and Turku). Blood samples are drawn and the oral glucose tolerance test (OGTT) done before and at 3 months of treatment, after which the treatment with placebo/metformin is continued another 6 months' period together with the appropriate infertility treatment. If pregnancy occurs, the OGTT is done at 7-8 weeks of pregnancy and the placebo/metformin treatment is continued until 12 weeks of pregnancy. The study has already started and is estimated to continue at least until the end of 2009. Power analysis indicated that a minimum of 60 pregnant patients are needed in each group to decrease the risk of miscarriage from 44% to the normal 15%.

Being tested
metformin
Keywords
Polycystic ovary syndrome, PCOS, Metformin, Miscarriage, Infertility, Complications of pregnancy
Medical subject headings
Polycystic Ovary Syndrome, Abortion, Spontaneous, Infertility, Toxemia, Diabetes, Gestational, Pregnancy Complications

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • metforminDrug

    The obese women will be randomized either to metformin (2g/day) or to placebo, and the non-obese either to metformin (1.5g/day) or to placebo. All subjects will be evaluated 1 to 7 days after spontaneous menstruation (oligomenorrheic patients), or at any other convenient time (amenorrheic subjects). After the treatment of 3 months with metformin/placebo alone, another appropriate infertility treatment will be combined with metformin/placebo (clomiphene, ovulation induction, insemination or in vitro fertilization) if no pregnancy has occurred. This treatment will be continued another 6 months' period. If pregnancy occurs, subjects will be re-examined at 7-8 weeks of gestation.

Study groups in NCT00994812
Study groupRoleWhat they receive
MetforminExperimentalNot described
Receives: Drug: metformin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Miscarriage rates

    Measured: at 7-8 weeks of pregnancy or later if miscarriage happens later

Secondary outcomes (3)

  1. Effect of metformin versus placebo on the time to be pregnant

    Measured: 3-6 months

  2. Effect of metformin versus placebo on the rates of toxemia during pregnancy

    Measured: 3 months after birth of the child

  3. Effects of metformin versus placebo on the rates of gestational diabetes during pregnancy

    Measured: 3 months after the birth of the child

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Oct 2009 (estimated)
  2. Study startAug 2002
  3. Primary completionDec 2009
  4. Study completionDec 2009

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
326 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00994812
Sponsor's protocol ID
T59108
Status last verified
Oct 2009
First submitted
9 Oct 2009
Last updated
23 Feb 2010
Results posted
No
Data monitoring committee
No

Publications

  • Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod. 2004 Nov;19(11):2474-83. doi: 10.1093/humrep/deh440. Epub 2004 Sep 9.

    PubMed 15358717

  • Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril. 2001 Jan;75(1):46-52. doi: 10.1016/s0015-0282(00)01666-6.

    PubMed 11163815

  • Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril. 2002 Mar;77(3):520-5. doi: 10.1016/s0015-0282(01)03202-2.

    PubMed 11872206

  • Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2002 Feb;87(2):524-9. doi: 10.1210/jcem.87.2.8207.

    PubMed 11836280

  • Palomba S, Orio F Jr, Falbo A, Manguso F, Russo T, Cascella T, Tolino A, Carmina E, Colao A, Zullo F. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005 Jul;90(7):4068-74. doi: 10.1210/jc.2005-0110. Epub 2005 Apr 19.

    PubMed 15840746

  • Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66. doi: 10.1056/NEJMoa063971.

    PubMed 17287476

  • Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ. 2006 Jun 24;332(7556):1485. doi: 10.1136/bmj.38867.631551.55. Epub 2006 Jun 12.

    PubMed 16769748

  • Lingaiah S, Morin-Papunen L, Risteli J, Tapanainen JS. Metformin decreases bone turnover markers in polycystic ovary syndrome: a post hoc study. Fertil Steril. 2019 Aug;112(2):362-370. doi: 10.1016/j.fertnstert.2019.04.013. Epub 2019 Jun 18.

    PubMed 31227287

  • Sova H, Puistola U, Morin-Papunen L, Karihtala P. Metformin decreases serum 8-hydroxy-2'-deoxyguanosine levels in polycystic ovary syndrome. Fertil Steril. 2013 Feb;99(2):593-8. doi: 10.1016/j.fertnstert.2012.10.013. Epub 2012 Oct 31.

    PubMed 23122829

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing metformin in people with Polycystic Ovary Syndrome and Miscarriage, run by University of Oulu at 5 sites in Finland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Feb 2010. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Finland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Miscarriage rates (time frame: at 7-8 weeks of pregnancy or later if miscarriage happens later). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00994812, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2010.

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