Pharmacogenetics of Metformin Action in PCOS

Overview[ - collapse ][ - ]

Purpose 1. The polycystic ovary syndrome is the major cause of infertility in the United States. Metformin has been shown to increase frequency of ovulations in PCOS, and is used in clinical practice to treat infertility, but some women with PCOS do not respond to metformin treatment. 2. Knowing that a specific gene predicts the effect of metformin on ovulation would facilitate more efficient and effective treatment of infertility in PCOS.
ConditionPolycystic Ovary Syndrome
InterventionDrug: Metformin 500 mg tablet
PhaseN/A
SponsorVirginia Commonwealth University
Responsible PartyVirginia Commonwealth University
ClinicalTrials.gov IdentifierNCT00703508
First ReceivedJune 20, 2008
Last UpdatedMay 17, 2013
Last verifiedMay 2013

Tracking Information[ + expand ][ + ]

First Received DateJune 20, 2008
Last Updated DateMay 17, 2013
Start DateJuly 2008
Estimated Primary Completion DateMarch 2014
Current Primary Outcome MeasuresDetermine if ovulations/9months/woman is greater in women with the G/G genotype of STK11 rs8111699 compared with women with the C/G and C/C genotypes. [Time Frame: 9 months] [Designated as safety issue: No]
Current Secondary Outcome MeasuresDetermine in which genotype(s) frequency of ovulation correlates with improvement in insulin sensitivity and/or reduction in total testosterone. [Time Frame: 9 months] [Designated as safety issue: No]

Descriptive Information[ + expand ][ + ]

Brief TitlePharmacogenetics of Metformin Action in PCOS
Official TitlePharmacogenetics of Metformin Action in PCOS
Brief Summary
1. The polycystic ovary syndrome is the major cause of infertility in the United States.
Metformin has been shown to increase frequency of ovulations in PCOS, and is used in
clinical practice to treat infertility, but some women with PCOS do not respond to
metformin treatment.

2. Knowing that a specific gene predicts the effect of metformin on ovulation would
facilitate more efficient and effective treatment of infertility in PCOS.
Detailed Description
The polycystic ovary syndrome (PCOS) affects approximately 6-10% of women of childbearing
age, i.e., 3.5-5.5 million women in the United States. PCOS is the most common endocrine
disturbance of young women and the major cause (75%) of anovulatory infertility in the
United States. We hypothesize that women with the polycystic ovary syndrome (PCOS) who have
the G/G genotype of single nucleotide polymorphism (SNP)_ rs8111699 in STK11 will exhibit a
significantly greater response to metformin, in terms of ovulation, compared with women with
either the C/G or C/C genotype. Specifically, we anticipate the frequency of ovulation
(defined by number of ovulations/9 months/subject) to be at least 2-fold higher in women
with the G/G STK11 genotype compared with women with either the C/G or C/C genotype.

To test this hypothesis, we will obtain DNA for STK11 genotyping in 36 women with PCOS who
are treated with metformin and carefully monitored for ovulation for 9 months. STK11
genotype status will be determined, and the ovulation rates in the G/G, G/C and C/C genotype
groups will be compared with one another. Our goal is to identify the genes that predict or
modify response to commonly prescribed medications that will allow physicians to better
choose among existing therapies and individualize treatment. While metformin has been shown
to increase ovulatory frequency in PCOS and is widely used in clinical practice to treat
infertility, a substantial number of women either do not respond or are slow to respond to
metformin treatment.

Knowing that a specific STK11 genotype predicts the effect of metformin on ovulation would
facilitate more efficient and effective treatment of infertility in PCOS.
Study TypeInterventional
Study PhaseN/A
Study DesignAllocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionPolycystic Ovary Syndrome
InterventionDrug: Metformin 500 mg tablet
Metformin 500 mg tablets; two tablets every 12 hours for 9 months
Other Names:
Glucophage
Study Arm (s)Experimental: Metformin
Metformin tablet, 500 mg/tablet, 2 tablets every twelve hours, 9 months duration

Recruitment Information[ + expand ][ + ]

Recruitment StatusActive, not recruiting
Estimated Enrollment36
Estimated Completion DateMarch 2014
Estimated Primary Completion DateApril 2013
Eligibility Criteria
Inclusion Criteria:

- Premenopausal women between 18-45 years of age and BMI less than 42

- Diagnosed with PCOS as defined by the Rotterdam criteria, which is a combination of
any two of the following three criteria: 1) chronic oligo- or amenorrhea (<8
menstrual periods annually); 2) biochemical or clinical androgen excess; and 3)
polycystic ovaries on ultrasonography -Normal thyroid function tests and serum
prolactin; and exclusion of 21 alpha hydroxylase deficiency by a fasting 17 alpha
hydroxyprogesterone less than 200 ng/dl -In acceptable health on the basis of
interview, medical history, physical examination, and laboratory tests (CBC,
SMA20,urinanalysis) -Able to provide signed, witnessed informed consent -Able to
comply with study requirements

Exclusion Criteria:

-Diabetes mellitus by fasting glucose or OGTT, or clinically significant pulmonary,
cardiac,renal,hepatic,neurologic,psychiatric,infectious,neoplastic and malignant disease
(other than non-melanoma skin cancer) -Current use of oral contraceptives; use of
fertility drugs within 6 months of study -Current or recent use (within 3 months prior to
study entry) of metformin -Documented or suspected recent (within one year)history of drug
abuse or alcoholism -Ingestion of any investigational drug within two months prior to
study onset.
GenderFemale
Ages18 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesUnited States

Administrative Information[ + expand ][ + ]

NCT Number NCT00703508
Other Study ID NumbersVCU IRB HM11153
Has Data Monitoring CommitteeYes
Information Provided ByVirginia Commonwealth University
Study SponsorVirginia Commonwealth University
CollaboratorsNot Provided
Investigators Principal Investigator: John E. Nestler, M.D. Virginia Commonwealth University
Verification DateMay 2013

Locations[ + expand ][ + ]

University Of Virginia General Clinical Research Center
Charlottesville, Virginia, United States, 22908
Virginia Commonwealth University
Richmond, Virginia, United States, 23298