Comparing the Effects of Oral Contraceptive Pills Versus Metformin

Study Overview
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Brief Summary
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To determine the effect of Oral Contraceptive Pills (OCP) verses Metformin verses OCP and Metformin on the prevalence of Metabolic Syndrome (MetS) and its components in overweight/obese women with Polycystic Ovary Syndrome (PCOS). The combination of OCP and metformin (OCP, through lowering androgens, and metformin, through improvement in insulin sensitivity) will affect the prevalence of MetS, thereby altering the risk profile for the development of diabetes and possible cardiovascular disease (CVD) in young women with PCOS.

Detailed Description
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The intervention will consist of randomizing subjects to one of three arms. Subjects will either be assigned to OCP + Placebo, Metformin + Placebo or OCP + Metformin. Metformin will be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses. Extended release pills will be utilized as they are associated with fewer gastrointestinal side effects. Subjects will begin with one tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose of metformin being 2000 mg. In regards to OCP, previous randomized clinical trials (RCTs) have shown that 20mcg ethinyl estradiol/norethindrone 1.0 mg was well tolerated. The study will utilize a 20mcg OCP but a less androgenic third generation progestin (desogestrel 0.15mg) with potentially lesser impact on lipids and insulin sensitivity. The OCP will be started on the first Sunday after spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce menses). Placebo pills will be administered to individuals randomized to OCP or metformin only in order to maintain study blinding. Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects

Official Title
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Comparing the Effects of Oral Contraceptive Pills Versus Metformin in the Medical Management of Overweight/Obese Women With Polycystic Ovary Syndrome

Conditions
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PCOS

Intervention / Treatment
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* Drug: OCP + Metformin
* Drug: OCP + Placebo
* Drug: Metformin + Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women ≥ 18 to ≤ 40 years of age (at the time of screening), with hyperandrogenic PCOS. Subjects will be diagnosed with PCOS defined by the most recent Rotterdam criteria based on: androgen excess (defined as an elevated serum T level or hirsutism, based on a Ferriman Gallwey score > 8 (note: > 2 for women of Asian descent) AND either: history of chronic anovulation (8 or fewer periods per year) AND/OR polycystic ovaries. BMI ≥ 25 kg/m² to ≤ 48 kg/m² obtained at screening visit. In good general health. Willing to avoid pregnancy for the duration of the study. Exclusion Criteria: Current pregnancy or desire of pregnancy during course of study Currently breastfeeding Known 21 hydroxylase deficiency Untreated thyroid disease (TSH <0.45 mlU/mL and > 4.5 mlU/mL) Untreated hyperprolactinemia (2 Levels>30 ng/ml at least one week apart) Type 1 or type 2 Diabetes Mellitus (elevated fasting serum glucose >126mg/dL on two occasions, poorly controlled diabetes (HgbA1C>6.5%), currently receiving anti-diabetic agents, or currently receiving metformin for treatment of diabetes Liver disease (AST/ALT>2 times normal or a total bilirubin >2.5 mg/dL) Renal disease (BUN>30 mg/dL or serum creatinine >1.4 mg/dL) Anemia (hemoglobin <10 mg/dL) History of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident Current history of alcohol abuse (>14drinks/week) Poorly controlled hypertension defined as average systolic blood pressure >= 150 mm Hg or average diastolic >=100 mm Hg obtained on three measurements obtained 5 minutes apart. If treated, average systolic blood pressure >=140 mm Hg or average diastolic >=90 mm Hg Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma TG>200mg/dl Use of lipid lowering or weight loss agents (subjects may wash out from weight loss agents) Current use of oral contraceptives, depo progestin, or hormonal implants Participation in any study of an investigational drug or device or biological agent within 30 days Suspected adrenal or ovarian tumor secreting androgens Suspected Cushing's syndrome Bariatric surgery procedure in the recent past (<12 months) Absolute contraindications to the use of hormonal contraceptives or metformin, 23. Subjects who are unable to comply with the study procedures, for instance due to mental illness, substance abuse, or participation in other studies.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits. No longer term follow-up is planned.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: OCP + Placebo<br>The OCP will be started on the first Sunday after spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce menses). Placebo pills will be administered to individuals randomized to OCP only in order to maintain study blinding. | Drug: OCP + Placebo<br>* This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.<br>|
| Active Comparator: Metformin + Placebo<br>Metformin will be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses. Extended release pills will be utilized as they are associated with fewer gastrointestinal side effects. Subjects will begin with one tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose of metformin being 2000 mg. Placebo pills will be administered to individuals randomized to metformin only in order to maintain study blinding. | Drug: Metformin + Placebo<br>* This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.<br>|
| Experimental: OCP + Metformin<br>The OCP will be started on the first Sunday after spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce menses). Metformin will be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses. Extended release pills will be utilized as they are associated with fewer gastrointestinal side effects. Subjects will begin with one tablet of metformin every night for 5 days, eventually building up to 4 tablets every night, with the maximum dose of metformin being 2000 mg. | Drug: OCP + Metformin<br>* This will be a three-arm, double-blind, double-dummy, multicenter, prospective, randomized clinical trial comparing OCP vs. Metformin vs. OCP + Metformin on the prevalence of MetS in women with PCOS. This 6-month study will consist of a screening visit, followed by 6 study visits (Subjects will undergo 6 in person study visits and life style modification counseling regarding diet and exercise. Phone contact will be made 2 weeks after randomization and at the end of each month when there is no in person visit to ensure study compliance with medications, keeping study logs and to review side effects). No longer term follow-up is planned.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of metabolic syndrome after randomizing to low dose OCP, metformin or OCP+metformin for 6 months. | Our primary goal is to determine the effect of 6 months' treatment with OCP vs. metformin vs. OCP + metformin on prevalence of MetS and its components in overweight / obese women. Implicit in the primary aim is clearly defining MetS, by NCEP ATPIII criteria as the presence of at least 3 of the following 5 criteria: TG≥150mg/dl, HDL-C<50mg/dl, BP≥130/≥85mmHg, WC>88cm and fasting glucose≥100mg/dl; and the goal of tracking safety of our interventions at all Phases of the study (through safety lab evaluations, vital signs and diaries) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HDL-C function | This will be assessed by measuring reverse cholesterol efflux capacity using validated ex vivo system | 6 months | 
| Changes in serum apoliproteins | This will be measured by NMR spectroscopy | 6 months | 
| Changes in serum adipokines in the 3 arms | Serum adipokines to be measured are adiponectin and leptin. These changes will be correlated with changes in serum and androgens and markers of insulin sensitivity | 6 months | 
| Changes in total and visceral body fat distribution in the 3 arms | Body fat distribution will be measured by DXA. These changes will be correlated with changes in serum and androgens and markers of insulin sensitivity | 6 months | 
| Changes in lipid particle size and number | This will be measured by NMR spectroscopy | 6 months | 
| Changes in serum markers of inflammation and free fatty acids. | Markers of inflammation to be measured are hsCRP, TNF α and IL6 | 6 months | 
| Changes in quality of life parameters in all 3 arms as assessed by PCOSQ | QOL will be measured by the Polycystic Ovary Syndrome Questionnaire (PCOSQ) | 6 months |