Comparing the Effects of Oral Contraceptive Pills Versus Metformin (COMET-PCOS)

October 14, 2025 updated by: Anuja Dokras

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
240

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United States
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 17033
        • Penn State/ Hershey Medical Center
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: 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.
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.
Active Comparator: 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.
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.
Experimental: 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.
Drug: 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.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of Participants With Metabolic Syndrome After 6 Months of Treatment Metformin or OCP+Metformin for 6 Months.
Time Frame: Baseline and 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)
Baseline and 6 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Changes in Serum Apoliprotein B From Baseline to 6 Months
Time Frame: Baseline and 6 months
This will be measured by NMR spectroscopy
Baseline and 6 months
Changes in Total Body Fat Distribution in the 3 Arms From Baseline to 6 Months
Time Frame: Baseline and 6 months
Body fat distribution will be measured by DXA. These changes will be correlated with changes in serum and androgens and markers of insulin sensitivity
Baseline and 6 months
Changes in Total Triglyceride-Rich Lipoprotein (TRLP) From Baseline to 6 Months
Time Frame: Baseline and 6 months
This will be measured by NMR spectroscopy
Baseline and 6 months
Changes in Serum Marker of Inflammation: Free Fatty Acids.
Time Frame: Baseline and 6 months
Measured by change in Free Fatty Acids
Baseline and 6 months
Changes in Quality of Life Parameters for Body Hair in All 3 Arms as Assessed by PCOSQ From Baseline to 6 Months
Time Frame: Baseline and 6 months
QOL will be measured by the Polycystic Ovary Syndrome Questionnaire (PCOSQ) Body Hair domain which has 5 items rated on a 7 point likert scale with a lower score representing a decreased quality of life. The total range is 7 to 35.
Baseline and 6 months
Changes in Visceral Body Fat Distribution in the 3 Arms
Time Frame: Baseline and 6 months
Body fat distribution will be measured by DXA. These changes will be correlated with changes in serum and androgens and markers of insulin sensitivity
Baseline and 6 months
Changes in Quality of Life Parameters for Weight in All 3 Arms as Assessed by PCOSQ From Baseline to 6 Months
Time Frame: Baseline and 6 months
QOL will be measured by the Polycystic Ovary Syndrome Questionnaire (PCOSQ) Weight domain which has 5 items rated on a 7 point likert scale with a lower score representing a decreased quality of life. The total range is 7 to 35.
Baseline and 6 months
Changes in Serum Adipokines in the 3 Arms
Time Frame: Baseline and 6 months
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.
Baseline and 6 months
Change in HDL-C Function
Time Frame: Baseline and 6 months
This will be assessed by measuring reverse cholesterol efflux capacity using validated ex vivo system.
Baseline and 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Anuja Dokras

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institutes of Health (NIH)
Milton S. Hershey Medical Center

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Anuja Dokras, MD, University of Pennsylvania

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 15, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 23, 2024

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 15, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 13, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 20, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 25, 2017

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 5, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 14, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 827819
  • 5R01HD091350-05 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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Conditions

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