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

Polycystic Ovary Syndrome Clinical Trial

— SHK002  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03905941
• Other study ID #: 21649
• Status: Recruiting
• Phase: Early Phase 1
• Start date: August 23, 2021
• Est. completion date: May 1, 2027

Study information

• Verified date: November 2023
• Source: University of Virginia
• Contact: Melissa Gilrain, BS
• Phone: 434-243-6911
• Email: pcos[@]virginia.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 88
• Est. completion date: May 1, 2027
• Est. primary completion date: April 1, 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 40 Years to 49 Years

Eligibility

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.

Related Conditions & MeSH terms

• Polycystic Ovary Syndrome

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	University of Virginia	Charlottesville	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
University of Virginia

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Total testosterone concentrations	ng/dL	baseline
Secondary	Total testosterone concentrations	ng/dL	6 months after each intervention
Secondary	Calculated free testosterone concentrations	pg/mL	baseline
Secondary	Calculated free testosterone concentrations	pg/mL	6 months after each intervention
Secondary	Sex hormone binding globulin	nmoL/L	baseline
Secondary	Sex hormone binding globulin	nmoL/L	6 months after each intervention
Secondary	LDL cholesterol level	mg/dL	baseline
Secondary	LDL cholesterol level	mg/dL	6 months after each intervention
Secondary	HDL cholesterol level	mg/dL	baseline
Secondary	HDL cholesterol level	mg/dL	6 months after each intervention
Secondary	Triglyceride level	mg/dL	baseline
Secondary	Triglyceride level	mg/dL	6 months after each intervention
Secondary	Blood pressure	mmHg	baseline
Secondary	Blood pressure	mmHg	6 months after each intervention
Secondary	Weight	kg	baseline
Secondary	Weight	kg	6 months after each intervention
Secondary	Body mass index	kg/meter square	baseline
Secondary	Body mass index	kg/meter square	6 months after each intervention
Secondary	waist-to-hip ratio	It is a ratio of waist and hip circumference	baseline
Secondary	waist-to-hip ratio	It is a ratio of waist and hip circumference	6 months after each intervention
Secondary	Matsuda index	It is an index to assess insulin sensitivity.	baseline
Secondary	Matsuda index	It is an index to assess insulin sensitivity.	6 months after each intervention
Secondary	Fasting insulin	uIU/mL	baseline
Secondary	Fasting insulin	uIU/mL	6 months after each intervention
Secondary	Fasting glucose	mg/dL	baseline
Secondary	Fasting glucose	mg/dL	6 months after each intervention
Secondary	2-hour glucose level during oral glucose tolerance test	mg/dL	baseline
Secondary	2-hour glucose level during oral glucose tolerance test	mg/dL	6 months after each intervention
Secondary	Hemoglobin A1c	percent	baseline
Secondary	Hemoglobin A1c	percent	6 months after each intervention
Secondary	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
Secondary	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