Comparing the Effects of Oral Contraceptive Pills Versus Metformin

Recruitment Status
COMPLETED - HAS RESULTS
(See Contacts and Locations)Verified August 2025 by Anuja Dokras
Sponsor
Anuja Dokras
Information Provided by (Responsible Party)
Anuja Dokras
Clinicaltrials.gov Identifier
NCT03229057
Other Study ID Numbers:
827819
First Submitted
July 12, 2017
First Posted
July 24, 2017
Results First Posted
January 22, 2025
Last Update Posted
November 4, 2025
Last Verified
August 2025

ClinicalTrials.gov processed this data on October 2025. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study 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

Condition or DiseaseIntervention/Treatment
PCOS
Drug: OCP + PlaceboDrug: Metformin + PlaceboDrug: OCP + Metformin

Study Design

Study TypeInterventional
Actual Enrollment240 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingTriple
Primary PurposeTreatment
Official TitleComparing the Effects of Oral Contraceptive Pills Versus Metformin in the Medical Management of Overweight/Obese Women With Polycystic Ovary Syndrome
Study Start DateJanuary 14, 2018
Actual Primary Completion DateJanuary 22, 2024
Actual Study Completion DateJuly 14, 2024

Groups and Cohorts

Group/CohortIntervention/Treatment
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.
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.
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.

Outcome Measures

Primary Outcome Measures
  1. Number of Participants With Metabolic Syndrome After 6 Months of Treatment 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)
Secondary Outcome Measures
  1. Changes in Serum Apoliprotein B From Baseline to 6 Months
    This will be measured by NMR spectroscopy
  2. 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.
  3. Changes in Total Body Fat Distribution in the 3 Arms From Baseline to 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
  4. Changes in Total Triglyceride-Rich Lipoprotein (TRLP) From Baseline to 6 Months
    This will be measured by NMR spectroscopy
  5. Changes in Serum Marker of Inflammation: Free Fatty Acids.
    Measured by change in Free Fatty Acids
  6. Changes in Quality of Life Parameters for Body Hair in All 3 Arms as Assessed by PCOSQ From Baseline to 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.
  7. Changes in 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
  8. Changes in Quality of Life Parameters for Weight in All 3 Arms as Assessed by PCOSQ From Baseline to 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.
  9. Change in HDL-C Function
    This will be assessed by measuring reverse cholesterol efflux capacity using validated ex vivo system.

Eligibility Criteria

Ages Eligible for Study(Adult)
Sexes Eligible for StudyFemale
Accepts Healthy VolunteersNo
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.

Contacts and Locations

Sponsors and CollaboratorsAnuja Dokras
Locations
Penn State/ Hershey Medical Center | Hershey Pennsylvania, United States, 17033University of Pennsylvania | Philadelphia Pennsylvania, United States, 19104
Investigators
Principal Investigator: Anuja Dokras, MD, University of Pennsylvania
Study Documents (Full Text)
Documents provided by Anuja Dokras: Study Protocol and Statistical Analysis Plan  November 29, 2021Documents provided by Anuja Dokras: Informed Consent Form  May 15, 2024