Clinical trial NCT03229057: Comparing the Effects of Oral Contraceptive Pills Versus Metformin
Official title: Comparing the Effects of Oral Contraceptive Pills Versus Metformin in the Medical Management of Overweight/Obese Women With Polycystic Ovary Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: PCOS
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Milton S. Hershey Medical Center
name: National Institutes of Health (NIH)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2017-07-25
Enrollment: 240
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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

Eligibility 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.

Primary outcomes:
measure: Number of Participants With Metabolic Syndrome After 6 Months of Treatment Metformin or OCP+Metformin for 6 Months.
timeFrame: Baseline and 6 months
Secondary outcomes:
measure: Changes in Serum Apoliprotein B From Baseline to 6 Months
timeFrame: Baseline and 6 months
measure: Changes in Serum Adipokines in the 3 Arms
timeFrame: Baseline and 6 months
measure: Changes in Total Body Fat Distribution in the 3 Arms From Baseline to 6 Months
timeFrame: Baseline and 6 months
measure: Changes in Total Triglyceride-Rich Lipoprotein (TRLP) From Baseline to 6 Months
timeFrame: Baseline and 6 months
measure: Changes in Serum Marker of Inflammation: Free Fatty Acids.
timeFrame: Baseline and 6 months
measure: Changes in Quality of Life Parameters for Body Hair in All 3 Arms as Assessed by PCOSQ From Baseline to 6 Months
timeFrame: Baseline and 6 months
measure: Changes in Visceral Body Fat Distribution in the 3 Arms
timeFrame: Baseline and 6 months
measure: Changes in Quality of Life Parameters for Weight in All 3 Arms as Assessed by PCOSQ From Baseline to 6 Months
timeFrame: Baseline and 6 months
measure: Change in HDL-C Function
timeFrame: Baseline and 6 months
Other outcomes:
Locations:
city: Hershey
country: United States
facility: Penn State/ Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Anuja Dokras, MD
role: PRINCIPAL_INVESTIGATOR
References: