Comparing the Effects of Oral Contraceptive Pills Versus Metformin

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

240 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-01-15

Study Completion Date

2024-07-15

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.

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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

Conditions

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PCOS

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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.

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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OCP + Placebo

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.

Group Type ACTIVE_COMPARATOR

OCP + Placebo

Intervention Type DRUG

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.

Metformin + Placebo

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.

Group Type ACTIVE_COMPARATOR

Metformin + Placebo

Intervention Type DRUG

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.

OCP + Metformin

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.

Group Type EXPERIMENTAL

OCP + Metformin

Intervention Type DRUG

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.

Interventions

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OCP + Metformin

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.

Intervention Type DRUG

OCP + Placebo

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.

Intervention Type DRUG

Metformin + Placebo

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.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. Women ≥ 18 to ≤ 40 years of age (at the time of screening), with hyperandrogenic PCOS.
2. Subjects will be diagnosed with PCOS defined by the most recent Rotterdam criteria based on:

1. 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:
2. history of chronic anovulation (8 or fewer periods per year)

AND/OR
3. polycystic ovaries.
3. BMI ≥ 25 kg/m² to ≤ 48 kg/m² obtained at screening visit.
4. In good general health.
5. Willing to avoid pregnancy for the duration of the study.

Exclusion Criteria

1. Current pregnancy or desire of pregnancy during course of study
2. Currently breastfeeding
3. Known 21 hydroxylase deficiency
4. Untreated thyroid disease (TSH \<0.45 mlU/mL and \> 4.5 mlU/mL)
5. Untreated hyperprolactinemia (2 Levels\>30 ng/ml at least one week apart)
6. 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
7. Liver disease (AST/ALT\>2 times normal or a total bilirubin \>2.5 mg/dL)
8. Renal disease (BUN\>30 mg/dL or serum creatinine \>1.4 mg/dL)
9. Anemia (hemoglobin \<10 mg/dL)
10. History of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident
11. Current history of alcohol abuse (\>14drinks/week)
12. 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
13. Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma
14. TG\>200mg/dl
15. Use of lipid lowering or weight loss agents (subjects may wash out from weight loss agents)
16. Current use of oral contraceptives, depo progestin, or hormonal implants
17. Participation in any study of an investigational drug or device or biological agent within 30 days
18. Suspected adrenal or ovarian tumor secreting androgens
19. Suspected Cushing's syndrome
20. Bariatric surgery procedure in the recent past (\<12 months)
21. 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.

Minimum Eligible Age

18 Years

Maximum Eligible Age

40 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No