Clinical trial NCT03905941: Relative Desirability of Metformin vs. Birth Control Pill in Treating PCOS in Women of Later Reproductive Age
Official title: Relative Desirability of Metformin vs. Birth Control Pill in Treating PCOS in Women of Later Reproductive Age
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Polycystic Ovary Syndrome
Keywords: Polycystic Ovary Syndrome
Lead sponsor: University of Virginia
Sponsor class: OTHER
First posted: 2019-04-08
Enrollment: 88
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 49
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a randomized, controlled, double blinded, controlled, crossover study.
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (PCOSQ) score
timeFrame: baseline
measure: Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (PCOSQ) score
timeFrame: 6 months after each intervention.
Secondary outcomes:
measure: Short Form (SF)-36 score
timeFrame: baseline
measure: Short Form (SF)-36 score
timeFrame: 6 months after each intervention
measure: General Anxiety Disorder (GAD)-7 score
timeFrame: baseline
measure: General Anxiety Disorder (GAD)-7 score
timeFrame: 6 months after each intervention
measure: Total testosterone concentrations
timeFrame: baseline
measure: Total testosterone concentrations
timeFrame: 6 months after each intervention
measure: Calculated free testosterone concentrations
timeFrame: baseline
measure: Calculated free testosterone concentrations
timeFrame: 6 months after each intervention
measure: Sex hormone binding globulin
timeFrame: baseline
measure: Sex hormone binding globulin
timeFrame: 6 months after each intervention
measure: LDL cholesterol level
timeFrame: baseline
measure: LDL cholesterol level
timeFrame: 6 months after each intervention
measure: HDL cholesterol level
timeFrame: baseline
measure: HDL cholesterol level
timeFrame: 6 months after each intervention
measure: Triglyceride level
timeFrame: baseline
measure: Triglyceride level
timeFrame: 6 months after each intervention
measure: Blood pressure
timeFrame: baseline
measure: Blood pressure
timeFrame: 6 months after each intervention
measure: Weight
timeFrame: baseline
measure: Weight
timeFrame: 6 months after each intervention
measure: Body mass index
timeFrame: baseline
measure: Body mass index
timeFrame: 6 months after each intervention
measure: waist-to-hip ratio
timeFrame: baseline
measure: waist-to-hip ratio
timeFrame: 6 months after each intervention
measure: Matsuda index
timeFrame: baseline
measure: Matsuda index
timeFrame: 6 months after each intervention
measure: Fasting insulin
timeFrame: baseline
measure: Fasting insulin
timeFrame: 6 months after each intervention
measure: Fasting glucose
timeFrame: baseline
measure: Fasting glucose
timeFrame: 6 months after each intervention
measure: 2-hour glucose level during oral glucose tolerance test
timeFrame: baseline
measure: 2-hour glucose level during oral glucose tolerance test
timeFrame: 6 months after each intervention
measure: Hemoglobin A1c
timeFrame: baseline
measure: Hemoglobin A1c
timeFrame: 6 months after each intervention
measure: Framingham risk score
timeFrame: baseline
measure: Framingham risk score
timeFrame: 6 months after each intervention
Other outcomes:
Locations:
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: University of Virginia
name: Chris McCartney, MD
role: PRINCIPAL_INVESTIGATOR
References: