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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03229057
Recruitment Status : Recruiting
First Posted : July 25, 2017
Last Update Posted : June 26, 2020
Sponsor:
Collaborators:
Milton S. Hershey Medical Center
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Anuja Dokras, University of Pennsylvania

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.


Condition or disease Intervention/treatment Phase
PCOS Drug: OCP + Metformin Drug: OCP + Placebo Drug: Metformin + Placebo Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Comparing the Effects of Oral Contraceptive Pills Versus Metformin in the Medical Management of Overweight/Obese Women With Polycystic Ovary Syndrome
Actual Study Start Date : January 1, 2018
Estimated Primary Completion Date : April 30, 2022
Estimated Study Completion Date : April 30, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. Prevalence of metabolic syndrome after randomizing to low dose OCP, metformin or OCP+metformin for 6 months. [ Time Frame: 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. Change in HDL-C function [ Time Frame: 6 months ]
    This will be assessed by measuring reverse cholesterol efflux capacity using validated ex vivo system

  2. Changes in serum apoliproteins [ Time Frame: 6 months ]
    This will be measured by NMR spectroscopy

  3. Changes in serum adipokines in the 3 arms [ Time Frame: 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

  4. Changes in total and visceral body fat distribution in the 3 arms [ Time Frame: 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

  5. Changes in lipid particle size and number [ Time Frame: 6 months ]
    This will be measured by NMR spectroscopy

  6. Changes in serum markers of inflammation and free fatty acids. [ Time Frame: 6 months ]
    Markers of inflammation to be measured are hsCRP, TNF α and IL6

  7. Changes in quality of life parameters in all 3 arms as assessed by PCOSQ [ Time Frame: 6 months ]
    QOL will be measured by the Polycystic Ovary Syndrome Questionnaire (PCOSQ)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03229057


Contacts
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Contact: Anuja Dokras, MD 215-615-0085 ADokras@obgyn.upenn.edu
Contact: Julia Vresilovic julia.vresilovic@pennmedicine.upenn.edu

Locations
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United States, Pennsylvania
Penn State/ Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033
Contact: Patsy Rawa    717-531-3692    prawa@pennstatehealth.psu.edu   
Principal Investigator: Richard Legro, MD         
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Anuja Dokras         
Sponsors and Collaborators
Anuja Dokras
Milton S. Hershey Medical Center
National Institutes of Health (NIH)
Investigators
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Principal Investigator: Anuja Dokras, MD University of Pennsylvania
Additional Information:
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Responsible Party: Anuja Dokras, Professor of Obstetrics and Gynecology, University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03229057    
Other Study ID Numbers: 827819
First Posted: July 25, 2017    Key Record Dates
Last Update Posted: June 26, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Metformin
Hypoglycemic Agents
Physiological Effects of Drugs