Comparing the Effects of Oral Contraceptive Pills Versus Metformin

NCT03229057 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 8278195R01HD091350-05
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

PCOS

Outcome Measures

Primary Outcomes (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)

  Baseline and 6 months

Secondary Outcomes (9)

• Changes in Serum Apoliprotein B From Baseline to 6 Months

  Baseline and 6 months

• Changes in Serum Adipokines in the 3 Arms

  Baseline and 6 months

• Changes in Total Body Fat Distribution in the 3 Arms From Baseline to 6 Months

  Baseline and 6 months

• Changes in Total Triglyceride-Rich Lipoprotein (TRLP) From Baseline to 6 Months

  Baseline and 6 months

• Changes in Serum Marker of Inflammation: Free Fatty Acids.

  Baseline and 6 months

Study Arms (3)

OCP + Placebo

ACTIVE COMPARATOR

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

Metformin + Placebo

ACTIVE COMPARATOR

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

OCP + Metformin

EXPERIMENTAL

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

Interventions

OCP + Metformin 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

OCP + Placebo 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 + Placebo

Metformin + Placebo 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

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Anuja Dokras: lead
• Milton S. Hershey Medical Center: collaborator
• National Institutes of Health (NIH): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (2)

Penn State/ Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• Dokras A, Coutifaris C, Remaley AT, Mehta NN, Playford MP, Kunselman AR, Stetter CC, Dodson WC, Legro RS. Impact of combined hormonal contraceptives and metformin on metabolic syndrome in women with hyperandrogenic polycystic ovary syndrome and obesity: The COMET-PCOS randomized clinical trial. PLoS Med. 2025 Dec 8;22(12):e1004662. doi: 10.1371/journal.pmed.1004662. eCollection 2025 Dec.

  PMID: 41359669 DERIVED

Related Links

• Related Info
• Related Info

MeSH Terms

Interventions

Metformin

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Limitations and Caveats

Two outcomes, Changes in HDL-C function assessed by measuring reverse cholesterol efflux capacity using validated ex vivo system and serum adipokines which are to be measured are adiponectin and leptin. We are currently looking for a vendor to run these assays.

Results Point of Contact

• Title: Dr Anuja Dokras
• Organization: University of Pennsylvania

adokras@pennmedicine.upenn.edu

215-615-0085

Study Officials

• Anuja Dokras, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Obstetrics and Gynecology

Model Details: 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.

Study Record Dates

• First Submitted: July 13, 2017
• First Posted: July 25, 2017
• Study Start: January 15, 2018
• Primary Completion: January 23, 2024
• Study Completion: July 15, 2024
• Last Updated: November 5, 2025
• Results First Posted: March 10, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)