Relative Desirability of Metformin vs. Birth Control Pill in Treating PCOS in Women of Later Reproductive Age (SHK002)

The goal of this study is to determine the relative desirability of metformin vs. oral combined hormonal contraceptives (OCs) in treating Polycystic Ovary Syndrome (PCOS) in women of later reproductive age. Polycystic Ovary Syndrome Questionnaire (PCOSQ) score will be used as a proxy for patient satisfaction. In light of their respective effects on the classic and metabolic facets of PCOS, metformin will provide non-inferior patient satisfaction compared to OCs in later reproductive age women with PCOS.

Study Overview

• Status: Recruiting
• Conditions: Polycystic Ovary Syndrome
• Intervention / Treatment: Drug: Metformin; Drug: Oral combined hormonal contraceptives

Detailed Description

This is a randomized, controlled, double-blinded, crossover study. The investigators will recruit women with PCOS in ages 40-49 yo. Subjects will be randomized to either receive metformin (2000 mg daily) or low dose oral contraceptives (OCs: 20 mcg ethinyl estradiol/norethindrone acetate 1mg) for a total of 6 months, and they will crossover to the other treatment for the following 6 months. Subjects will have the following assessed at baseline and 6 months after each study medication: blood pressure, weight, waist-to-hip ratio (WHR), average intermenstrual cycle length (in the previous 3 months), Ferriman-Gallwey score (as a measure of hirsutism), total testosterone (T), sex hormone binding globulin, calculated free T, fasting insulin, fasting glucose, 2-h glucose (during oral glucose tolerance test), Matsuda index, HgA1c, LDL-cholesterol, HDL-cholesterol, triglycerides, estimated cardiovascular risk (Framingham risk score), health-related quality of life using both PCOS questionnaire (PCOSQ) and the Short-Form Health Survey (SF-36), and severity of anxiety using Generalized Anxiety Disorder-7 (GAD-7) questionnaire. For safety surveillance, the investigators will measure electrolyte levels, renal function, liver function, and pregnancy tests immediately before study mediation initiation and every 3 months. For statistical analysis, per PCOSQ domain, the post-treatment QoL scores will be analyzed via a linear mixed model (LMM), in which the LMM will be specified in accordance with a 2 treatment by 2 period crossover design. The investigators determined that if 73 subjects complete the study, the investigators expect to have at least an 80% chance of rejecting the null hypothesis that QoL is inferior with metformin therapy vs. OCs.

• Study Type: Interventional
• Enrollment (Estimated): 88
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Melissa Gilrain, BS; Phone Number: 434-243-6911; Email: pcos@virginia.edu
• Study Contact Backup: Name: Chris McCartney, MD; Phone Number: 434-243-6911; Email: cm2hq@virginia.edu

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22901
      • Recruiting
      • University of Virginia
      • Contact: Melissa Gilrain, BS; Phone Number: 434-243-6911; Email: pcos@virginia.edu
      • Contact: Chris McCartney, MD; Phone Number: 434-243-6911; Email: cm2hq@virginia.edu
      • Principal Investigator: Chris McCartney, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 49 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Women with PCOS aged 40-49 years. Subject is considered to have PCOS if she has current or verifiable history of: a) clinical and/or biochemical evidence of hyperandrogenism plus b) oligomenorrhea or irregular menstruation (substantially inconsistent menstrual cycle length). Subjects with fewer than 10 menses/year or average menstrual cycle length >35 days are allowed to participate if they have a compelling past history of oligomenorrhea (average menstrual cycle length >45 days or fewer than 9 menses/year) or irregular menstruation.
• Screening safety labs within normal reference ranges although mild abnormalities that are common in obesity and/or hyperandrogenism will not be grounds for exclusion (see exclusion criteria).
• Subjects must be willing and able to provide written informed consent.
• Willingness to strictly avoid pregnancy (using non-hormonal methods) during the time of the study
• Willingness and ability to comply with scheduled visits and study procedures

Exclusion Criteria:

• Postmenopausal status (i.e., absence of periods for previous year plus elevated follicle stimulating hormone [FSH] level)
• Biochemical evidence for perimenopause as defined by an anti-Mullerian hormone <0.5 ng/mL. As an alternative, cycle day 3 FSH > 9 IU/L (with concomitant estradiol level >80 pg/mL), if this testing is available, will serve as evidence of perimenopause status. NOTE: If FSH >9 IU/L on screening (but it is not cycle day 3), FSH and estradiol will be repeated on cycle day 3
• History of hysterectomy and/or bilateral oophorectomy
• BMI ≥ 40 kg/m2
• Inability to comprehend what will be done during the study or why it will be done.
• Being a study of older women with PCOS, children and men will be excluded.
• Pregnancy or lactation within the past 6 months. Subjects with a positive pregnancy test will be informed of the result by the screening physician.
• Prisoners.
• History of (or clinical evidence for) Cushing's syndrome or adrenal insufficiency.
• History of congenital adrenal hyperplasia or 17-hydroxyprogesterone (17-OHP) >200 ng/dL, which suggest the possibility of congenital adrenal hyperplasia. 17-OHP will be collected during follicular phase. NOTE: if a 17-OHP >200 ng/dL and is confirmed on repeat testing, an ACTH-stimulated 17-OHP <1000 ng/dL will be required for study participation.
• Total testosterone >150 ng/dL, which suggests the possibility of virilizing neoplasm.
• DHEA-S greater than 1.5 times the upper limit of normal range (mild elevations may be seen in PCOS, so elevations < 1.5 times the upper limit of normal will be accepted in these groups).
• Virilization
• Diagnosis of diabetes mellitus (DM), fasting glucose ≥ 126 mg/dL, or a hemoglobin A1c of ≥ 6.5%.
• Abnormal thyroid stimulating hormone (TSH). Subjects with stable and adequately-treated hypothyroidism, reflected by normal TSH values, will not be excluded.
• Moderate to severe hyperprolactinemia. Mild prolactin elevations may be seen in PCOS, and elevations < 1.5 times the upper limit of normal will be accepted in this group.
• Persistent liver abnormalities, with the exception that mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome. Mild transaminase elevations may be seen in women with obesity, so elevations <1.5 times the upper limit of normal will be accepted in this group.
• Persistent hematocrit <36% and hemoglobin <12 g/dL.
• Abnormal sodium, potassium, or bicarbonate concentrations or elevated creatinine concentration.
• Significant history of pulmonary dysfunction (e.g., asthma or COPD requiring intermittent systemic corticosteroid, pulmonary hypertension, etc.).
• History of known or suspected congestive heart failure.
• History of known or suspected ischemic heart disease or cerebrovascular disease.
• History of hypertension.
• History of uncontrolled/untreated dyslipidemia. Subjects with stable and adequately treated dyslipidemia reflected by normal lipid panel values will not be excluded.
• History of complicated valvular heart disease (e.g. pulmonary hypertension, risk of atrial fibrillation, history of subacute bacterial endocarditis)
• History of stroke
• History of smoking
• History of severe cirrhosis or liver tumor (e.g. hepatocellular adenoma or malignant hepatoma).
• Use of anticonvulsants, rifampicin or rifabutin therapy. The interaction of these drugs with OCs will not be harmful to the subjects, but it will reduce the effectiveness of OCs.
• History of venous thromboembolism (e.g. deep venous thrombosis (DVT), pulmonary embolism (PE)).
• Personal history of blood clotting disorders (e.g., protein C, protein S, positive antiphospholipid antibodies).
• First-degree relative history of blood clotting disorder, unless the same disorder has been formally excluded for the study subject.
• History of migraine headaches.
• History of breast, ovarian, or endometrial cancer.
• Note: If endometrial thickness on transvaginal ultrasound is >8 mm in the proliferative (follicular) phase or >14 mm in the secretory (luteal) phase, the subject will be referred to a gynecologist for further evaluation (38). These particular subjects will be required to obtain a clearance from their gynecologist to participate in this study.
• Note: Any abnormal labs may be repeated to exclude a lab error.
• No medications known to affect the reproductive system can be taken in the 2 months prior to screening and in the 3 months prior to the study. Such medications include oral contraceptive pills, metformin, progestins, glucocorticoids, anti-psychotics, and/or mood stabilizers that are known to cause hormone abnormalities.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin then oral combined hormonal contraceptives; Subjects will take metformin 2000 mg/day for the first 6 months, followed by 6 months of oral combined hormonal contraceptive (OCs) with a combination of ethinyl estradiol 20 mcg/norethindrone acetate 1 mg.	Drug: Metformin; Metformin 2000 mg/day will be used in this study. Metformin is a antihyperglycemic agent that is used as a first line medical therapy to treat type 2 diabetes mellitus. It is also used to prevent progression of impaired glucose tolerance. It decrease hepatic glucose production and increase insulin sensitivity.; Drug: Oral combined hormonal contraceptives; Oral combined hormonal contraceptive (OCs) with a combination of ethinyl estradiol 20 mcg/norethindrone acetate 1 mg will be used in this study. OCs are normally used to prevent pregnancy by suppressing ovulation and to prevent endometrial hyperplasia by inducing regular "withdrawal" bleeding. OCs help control both clinical and biochemical hyperandrogenism in PCOS and are considered first line medical therapy until the age of menopause.
Active Comparator: Oral combined hormonal contraceptives then metformin; Subjects will take oral combined hormonal contraceptive (OCs) with a combination of ethinyl estradiol 20 mcg/norethindrone acetate 1 mg for the first 6 months, followed by 6 months of metformin 2000 mg/day.	Drug: Metformin; Metformin 2000 mg/day will be used in this study. Metformin is a antihyperglycemic agent that is used as a first line medical therapy to treat type 2 diabetes mellitus. It is also used to prevent progression of impaired glucose tolerance. It decrease hepatic glucose production and increase insulin sensitivity.; Drug: Oral combined hormonal contraceptives; Oral combined hormonal contraceptive (OCs) with a combination of ethinyl estradiol 20 mcg/norethindrone acetate 1 mg will be used in this study. OCs are normally used to prevent pregnancy by suppressing ovulation and to prevent endometrial hyperplasia by inducing regular "withdrawal" bleeding. OCs help control both clinical and biochemical hyperandrogenism in PCOS and are considered first line medical therapy until the age of menopause.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (PCOSQ) score	It is a 7-point scale questionnaire assessing health-related quality of life specific to PCOS in 5 different domains, with "7" representing optimal function and "1" representing poorest function.	baseline
Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (PCOSQ) score	It is a 7-point scale questionnaire assessing health-related quality of life specific to PCOS in 5 different domains, with "7" representing optimal function and "1" representing poorest function.	6 months after each intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Short Form (SF)-36 score	It consists of 36 items and has eight scaled scores (transformed into 0-100 scale). It assesses health related quality of life (general). The increasing score indicates better health status.	baseline
Short Form (SF)-36 score	It consists of 36 items and has eight scaled scores (transformed into 0-100 scale). It assesses health related quality of life (general). The increasing score indicates better health status.	6 months after each intervention
General Anxiety Disorder (GAD)-7 score	It consists of 7 items with a scale of 0-3, and they are summed up to a total score. Increasing scores mean a greater functional impairment.	baseline
General Anxiety Disorder (GAD)-7 score	It consists of 7 items with a scale of 0-3, and they are summed up to a total score. Increasing scores mean a greater functional impairment.	6 months after each intervention
Total testosterone concentrations	ng/dL	baseline
Total testosterone concentrations	ng/dL	6 months after each intervention
Calculated free testosterone concentrations	pg/mL	baseline
Calculated free testosterone concentrations	pg/mL	6 months after each intervention
Sex hormone binding globulin	nmoL/L	baseline
Sex hormone binding globulin	nmoL/L	6 months after each intervention
LDL cholesterol level	mg/dL	baseline
LDL cholesterol level	mg/dL	6 months after each intervention
HDL cholesterol level	mg/dL	baseline
HDL cholesterol level	mg/dL	6 months after each intervention
Triglyceride level	mg/dL	baseline
Triglyceride level	mg/dL	6 months after each intervention
Blood pressure	mmHg	baseline
Blood pressure	mmHg	6 months after each intervention
Weight	kg	baseline
Weight	kg	6 months after each intervention
Body mass index	kg/meter square	baseline
Body mass index	kg/meter square	6 months after each intervention
waist-to-hip ratio	It is a ratio of waist and hip circumference	baseline
waist-to-hip ratio	It is a ratio of waist and hip circumference	6 months after each intervention
Matsuda index	It is an index to assess insulin sensitivity.	baseline
Matsuda index	It is an index to assess insulin sensitivity.	6 months after each intervention
Fasting insulin	uIU/mL	baseline
Fasting insulin	uIU/mL	6 months after each intervention
Fasting glucose	mg/dL	baseline
Fasting glucose	mg/dL	6 months after each intervention
2-hour glucose level during oral glucose tolerance test	mg/dL	baseline
2-hour glucose level during oral glucose tolerance test	mg/dL	6 months after each intervention
Hemoglobin A1c	percent	baseline
Hemoglobin A1c	percent	6 months after each intervention
Framingham risk score	This is a risk assessing measure that estimates the 10 year cardiovascular risk for an individual. There is no scale for this. A total risk (in percentage) will be calculated.	baseline
Framingham risk score	This is a risk assessing measure that estimates the 10 year cardiovascular risk for an individual. There is no scale for this. A total risk (in percentage) will be calculated.	6 months after each intervention

Collaborators and Investigators

• Sponsor: University of Virginia
• Investigators: Principal Investigator: Chris McCartney, MD, University of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2021
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: April 2, 2019
• First Submitted That Met QC Criteria: April 5, 2019
• First Posted (Actual): April 8, 2019

Study Record Updates

• Last Update Posted (Actual): November 3, 2023
• Last Update Submitted That Met QC Criteria: November 1, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Polycystic Ovary Syndrome
• Additional Relevant MeSH Terms: Neoplasms; Endocrine System Diseases; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Polycystic Ovary Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Reproductive Control Agents; Metformin; Contraceptive Agents
• Other Study ID Numbers: 21649

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.: No