Pharmacogenetics of Metformin Action in PCOS

• Sponsor: Virginia Commonwealth University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00703508
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 55
• Locations: 2
• Arm: 1
• Duration (Months): 68
• Patients Per Site: 27.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome	Drug: Metformin 500 mg tablet	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacogenetics of Metformin Action in PCOS
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin Metformin tablet, 500 mg/tablet, 2 tablets every twelve hours, 9 months duration	Drug: Metformin 500 mg tablet; Metformin 500 mg tablets; two tablets every 12 hours for 9 months; Other Names: Glucophage

Outcome Measures

Primary Outcome Measures

1. Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G) [9 months]

   Responders were defined as those that had a doubling of baseline ovulation rate estimated by self-report of menstrual history.

2. Ovulation Rate Over Study Duration for STK11 Genotypes CC, CG and GG [9 months]

   Ovulations were determined by measurement of daily urine pregnanediol-3-glucuronide or weekly progesterone levels over 6-9 months of study duration for each participant. The ovulation rate was calculated as the number of confirmed ovulation events per months of study participation.

Secondary Outcome Measures

1. Determine in Which Genotype(s) Frequency of Ovulation Correlates With Improvement in Reduction in Total Testosterone and Insulin Sensitivity as Measured by the Matsuda Index. [9 months]

   Bivariate fit (RSquare with P values) of ovulation rate post treatment by change in total testosterone and Matsuda Index for each of the 3 genotypes (G/G, C/G, C/C)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Of Virginia General Clinical Research Center	Charlottesville	Virginia	United States	22908
2	Virginia Commonwealth University	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• Virginia Commonwealth University
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: John E. Nestler, M.D., Virginia Commonwealth University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT00703508
• Other Study ID Numbers: HM11153; 2U54HD034449
• First Posted: Jun 23, 2008
• Last Update Posted: Jun 14, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Virginia Commonwealth University: PCOS
• Additional relevant MeSH terms: Polycystic Ovary Syndrome; Metformin

Study Results

Participant Flow

Pre-assignment Detail	55 subjects were enrolled, however some subjects failed to meet eligibility criteria resulting in 26 subjects initiating and completing all study phases.

Arm/Group Title	Metformin
Arm/Group Description	Metformin tablet, 500 mg/tablet, 2 tablets every twelve hours, 9 months duration Metformin 500 mg tablet: Metformin 500 mg tablets; two tablets every 12 hours for 9 months
Period Title: Overall Study
STARTED	26
COMPLETED	26
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Metformin
Arm/Group Description	Metformin tablet, 500 mg/tablet, 2 tablets every twelve hours, 9 months duration Metformin 500 mg tablet: Metformin 500 mg tablets; two tablets every 12 hours for 9 months
Overall Participants	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.9 (4.2)
Sex: Female, Male (Count of Participants)
Female	26 100%
Male	0 0%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	35.0 (7.6)

Outcome Measures

1. Primary Outcome

Title	Number of Responders/Non-responders for Each STK11 rs8111699 Genotype (C/G, C/C, G/G)
Description	Responders were defined as those that had a doubling of baseline ovulation rate estimated by self-report of menstrual history.
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	G/G Genotype	C/G Genotype	C/C Genotype
Arm/Group Description	Metformin tablet, 500 mg per tablet, 2 tablets every 12 hours	Metformin tablet, 500 mg per tablet, 2 tablets every 12 hours	Metformin tablet, 500 mg per tablet, 2 tablets every 12 hours
Measure Participants	26	26	26
responders	6 23.1%	7 NaN	5 NaN
non-responders	3 11.5%	4 NaN	1 NaN

2. Primary Outcome

Title	Ovulation Rate Over Study Duration for STK11 Genotypes CC, CG and GG
Description	Ovulations were determined by measurement of daily urine pregnanediol-3-glucuronide or weekly progesterone levels over 6-9 months of study duration for each participant. The ovulation rate was calculated as the number of confirmed ovulation events per months of study participation.
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	G/G Genotype	C/G Genotype	C/C Genotype
Arm/Group Description	Metformin tablet, 500 mg per tablet, 2 tablets every 12 hours	Metformin tablet, 500 mg per tablet, 2 tablets every 12 hours	Metformin tablet, 500 mg per tablet, 2 tablets every 12 hours
Measure Participants	9	11	6
Mean (Standard Deviation) [ovulations/month]	0.47 (0.310)	0.36 (0.396)	0.34 (0.336)

3. Secondary Outcome

Title	Determine in Which Genotype(s) Frequency of Ovulation Correlates With Improvement in Reduction in Total Testosterone and Insulin Sensitivity as Measured by the Matsuda Index.
Description	Bivariate fit (RSquare with P values) of ovulation rate post treatment by change in total testosterone and Matsuda Index for each of the 3 genotypes (G/G, C/G, C/C)
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

Individuals that were lost to follow up had missing data on testosterone and OGTT (oral glucose tolerance testing) for Matsuda index.

Arm/Group Title	G/G Genotype	C/G Genotype	C/C Genotype
Arm/Group Description	Metformin tablet, 500 mg per tablet, 2 tablets every 12 hours	Metformin tablet, 500 mg per tablet, 2 tablets every 12 hours	Metformin tablet, 500 mg per tablet, 2 tablets every 12 hours
Measure Participants	9	7	3
Ovulation rate vs Testosterone post treatment	0.138956	0.035449	0.049263
Ovulation rate vs Matsuda Index post treatment	0.27144	0.01918	0.132059

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	G/G Genotype
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0234
	Comments	Ovulation rate vs Testosterone post-treatment, threshold for statistical significance = p<0.05
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	C/G Genotype
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0740
	Comments	Ovulation rate vs Testosterone post-treatment, threshold for statistical significance = p<0.05
	Method	Regression, Linear
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	C/C Genotype
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4698
	Comments	Ovulation rate vs Testosterone post-treatment, threshold for statistical significance = p<0.05
	Method	Regression, Linear
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	G/G Genotype
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1180
	Comments	Ovulation rate vs Matsuda Index post-treatment, threshold for statistical significance = p < 0.05.
	Method	Regression, Linear
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	C/G Genotype
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0311
	Comments	Ovulation rate vs Matsuda Index post-treatment, threshold for statistical significance = p < 0.05.
	Method	Regression, Linear
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	C/C Genotype
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1586
	Comments	Ovulation rate vs Matsuda Index post-treatment, threshold for statistical significance = p < 0.05.
	Method	Regression, Linear
	Comments

Adverse Events

Time Frame	For entire 9 months of study plus 30 days after study completion
Arm/Group Title	Metformin
Arm/Group Description	Metformin tablet, 500 mg/tablet, 2 tablets every twelve hours, 9 months duration Metformin 500 mg tablet: Metformin 500 mg tablets; two tablets every 12 hours for 9 months
All Cause Mortality
	Metformin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Metformin
	Affected / at Risk (%)	# Events
Total	0/26 (0%)
Other (Not Including Serious) Adverse Events
	Metformin
	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)
Blood and lymphatic system disorders
Anemia	1/26 (3.8%)	1

Limitations/Caveats

Interpretations of our findings are limited by our small sample size.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.