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This study will be a Phase 3, randomized, three-cycle, double-blind, placebo-controlled, parallel group, multiple-dose design.

The study design has four phases: Screening Period; Open-Label Estrogen-Priming Period (Run-In Period); Blinded Treatment Period; and Follow-Up. The Open Label Priming Period and Blinded Treatment Period cover a total of three 28-day cycles. Clinical evaluations will be performed at the following time points:

Screening Period:

• Screening Period (approximately 42 Days)

Open-Label Estrogen Priming Period (Run In Period):

* Visit 1 Baseline (Cycle 1, Day 1)
* Telephone Interview (Cycle 1, Day 28 \[- 3 d to ±1d\])

Blinded Treatment Period:

* Visit 2 Randomization (Cycle 2, Day 12 \[±2d\])
* Visit 3 Interim (Cycle 3, Day 12 \[±2d\])
* Visit 4 End of treatment (Cycle 3, Day 24 \[±1d\])

Follow-Up Period:

* Visit 5 Follow-Up (Approximately 10 days after the last treatment)
* Telephone Interview (Approximately 2-4 weeks after completion of progestin course) (Only applies to subjects receiving an approved progestin therapy for proliferative endometrium, as determined by biopsy.)

A Phase 3, Randomized, Three-Cycle, Double-Blind, Placebo-Controlled Study to Evaluate Induction of Secretory Conversion of Endometrium and Withdrawal Bleeding for Secondary Amenorrhea

A Phase 3, Randomized, Three-Cycle, Double-Blind, Placebo-Controlled Study to Evaluate Induction of Secretory Conversion of Endometrium and Withdrawal Bleeding After Administration of TX-12-002-HR in Estrogen-Primed Women With Secondary Amenorrhea

TherapeuticsMD

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Genital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Hypoglycemic Agents

Insulin

Insulin, Globin Zinc

Frequently Sampled Intravenous Glucose Tolerance Test with minimal model analysis (MINMOD FSIVGTT)

Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT)

The purpose of this research study is to see if there are differences between African-American and Caucasian girls with Polycystic Ovary Syndrome (PCOS) in how their bodies respond to a type of sugar, called glucose, the body's main source of energy. PCOS is one of the most common endocrine disorders among females. Features can include anovulation (eggs are not released from the ovaries) resulting in irregular menstrual periods, excessive amounts of androgenic (male) hormones resulting in acne and hirsutism (excessive hair growth on the face and body), and polycystic ovaries (small sac-like structures \[cysts\] on your ovaries) seen on ultrasound. Girls with PCOS also have higher levels of insulin in their bodies (called hyperinsulinism) but are not able to use insulin very well (called insulin resistance) resulting in an increased risk of diabetes. Diabetes is when you have high levels of glucose (sugar) in your blood. Many studies have looked at how bodies respond to glucose and have shown that compared to Caucasians, healthy African-Americans produce much more insulin (hyperinsulinism) but are not able to use it as well (insulin resistance) in childhood, adolescence, and adulthood. Insulin is a hormone that helps glucose move from the blood into the muscles for the body to use as energy. PCOS is associated with increased levels of insulin (hyperinsulinism) and not being able to use it as well (insulin resistance). So we want to see if there is a difference in insulin production (secretion) and insulin resistance between African-Americans and Caucasians girls with PCOS. To do this, we will look at blood glucose and insulin levels in response to giving glucose in African-American and Caucasian girls who have PCOS. The results of this study may ultimately help to more effectively target treatment therapy in individuals with PCOS that have increased insulin secretion and/or increased insulin resistance.

PCOS is the most common endocrine abnormality of reproductive-aged women in the United States, affecting approximately 5 million women (1). The exact prevalence of PCOS in the adolescent population is unknown mainly attributed to the diagnostic challenge PCOS presents as the characteristics of normal puberty overlap with the signs and symptoms of PCOS (2). The key features of PCOS include menstrual irregularity, hyper¬androgenism, and polycystic ovarian morphology on ultrasound. However, clinical presentation may vary. It is a complex heterogeneous condition with life-long psychological, reproductive, and metabolic manifestations that impact a woman's health throughout her lifespan. PCOS is associated with major metabolic consequences including hyperinsulinism (i.e. increased insulin secretion), insulin resistance (i.e. decreased insulin sensitivity), obesity, type 2 diabetes mellitus, dyslipidemia, cardiovascular disease, endothelial dysfunction, defective fibrino¬lysis, as well as endometrial carcinoma (3).

Particular disease processes show a predilection for certain racial and ethnic groups. African-American \[AA\] adults are at increased risk of obesity, type 2 diabetes mellitus, cardiovascular disease mortality, and hyper¬tension compared to Caucasian \[CA\] adults. Past studies (4-9) have found that AAs have increased insulin secretion and decreased insulin sensitivity compared to their CA counterparts in adolescence and adulthood and even in childhood. These findings are secondary to the combination of increased insulin secretion and resistance with decreased insulin sensitivity and clearance noted in African-Americans. It is this combination of altered glucose metabolism that places AAs at increased risk of cardiovascular and metabolic morbidity. It has been proposed that hyperinsulinism or increased insulin secretion is a compensatory response by the pancreatic β-cell to increased insulin resistance. However, it has also been speculated that it is insulin resistance that is the compensatory response occurring in response to insulin hyper-secretion caused by pancreatic β-cell dysregulation (10-11).

Hyperinsulinism and insulin resistance are known inherent features of PCOS. Several studies have demonstrated significant hyperinsulinism with insulin resistance and lowered insulin sensitivity in adolescents and adults with PCOS when compared to BMI-matched healthy control subjects (12-18). Marked differences in insulin sensitivity/resistance and PCOS phenotype have been reported in adults of different races/ethnicities with PCOS (19-23), however; other studies have refuted these claims (24-27). The objective of this study is to examine the differences in insulin secretion between AA and CA adolescents with PCOS. We will also examine differences in insulin sensitivity/resistance between AA and CA adolescents with PCOS.

Primary Aim: To determine the influence of racial/ethnic background on insulin secretion in adolescent females with PCOS.

Secondary Aim: To determine the influence of racial/ethnic background on insulin sensitivity/resistance in adolescent females with PCOS.

Hypothesis: AA adolescent females with PCOS will have increased insulin secretion and decreased insulin sensitivity (i.e. increased insulin resistance) compared to CA adolescent females with PCOS.

To address this hypothesis, we will utilize one of the gold standards endorsed by the American Diabetes Association that satisfactorily assess insulin secretion and insulin sensitivity/resistance. The method utilized in this study is the frequently sampled intravenous glucose tolerance test with minimal model analysis (MINMOD FSIVGTT) (28-32). Using the data that is gathered as part of our primary and secondary aims, we will also conduct an exploratory analysis to examine the influence of PCOS phenotype on insulin secretion and insulin sensitivity/resistance and the influence of racial/ethnic background on PCOS phenotype.

Insulin Differences Between African-American and Caucasian Female Adolescents With Polycystic Ovary Syndrome (PCOS)

Differences in Insulin Secretion and Insulin Sensitivity/Resistance in African-American and Caucasian Adolescent Females With Polycystic Ovary Syndrome

Using the data that is gathered as part of our primary and secondary aims, we will also conduct an exploratory analysis to examine the influence of PCOS phenotype on insulin secretion and insulin sensitivity/resistance and the influence of racial/ethnic background on PCOS phenotype.

The objective of this study is to examine the differences in insulin secretion between AA and CA adolescents with PCOS. Primary Aim: To determine the influence of racial/ethnic background on insulin secretion in adolescent females with PCOS.

The objective of this study is to examine differences in insulin sensitivity/resistance between AA and CA adolescents with PCOS. Secondary Aim: To determine the influence of racial/ethnic background on insulin sensitivity/resistance in adolescent females with PCOS.

Nationwide Children's Hospital

Pediatric Endocrinology Fellow

300 mg (3x100mg capsules) by mouth once daily at bedtime for 10 days X 3 cycles

PROMETRIUM® 300 mg

400 mg (4x100mg capsules) by mouth once daily at bedtime for 10 days X 3 cycles

PROMETRIUM® 400 mg

Global Clinical Director Solvay

To evaluate the efficacy and safety of 300 mg and 400 mg doses of PROMETRIUM® capsules in women of reproductive age with secondary amenorrhea

Safety and Efficacy of PROMETRIUM® Capsules in Induction of Secretory Conversion

Evaluation of Safety and Efficacy of PROMETRIUM® Capsules in Induction of Secretory Conversion of Endometrium and Withdrawal Bleeding in Subjects With Secondary Amenorrhea

Endometrial biopsy results were classified as : Secretory (Complete or partial), Non-secretory, Unable to determine or Unknown after an evaluation of morphologic criteria.

This measure is the number of subjects with withdrawal bleeding using Last Observation Carried Forward (LOCF) after first and second cycle.

The intensity of withdrawal bleeding was classified by: None, Spotting, Light, Moderate, Heavy

The numbers of days the subjects actually bled after the end of the first treatment cycle.

The numbers of days the subjects actually bled after the end of the second treatment cycle

The number of days between the first cycle of treatment and the withdrawal bleeding.

The number of days between the second cycle of treatment and the withdrawal bleeding

Solvay Pharmaceuticals

Cindy Lane

The safety analysis is presented on the safety sample meaning the number of patients who were randomized and received at least one dose of study medication.

Prometrium 300 mg/Day

Prometrium 400 mg/Day

Total

The participant flow chart was done on all Randomized subjects set (i.e. subjects who received at least one dose of open-label study medication) . The baseline results are presented on the Full Analysis set (i.e. subjects randomized with at least one post-baseline evaluable efficacy assessment).

Age Continuous

Sex: Female, Male

United States

Region of Enrollment

Sven Voet - Global Communication

Secretory

Non-Secretory

Unable to determine

Unknown

The analysis was done on the Full Analysis Sample defined as subjects who received at least one dose of treatment and with at least one post-baseline evaluable efficacy assessment. Only summary statistics were generated.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase 3, Randomized, Three-Cycle, Double-Blind, Placebo-Controlled Study to Evaluate Induction of Secretory Conversion of Endometrium and Withdrawal Bleeding for Secondary Amenorrhea	NCT02019589	Secondary Ameno...	Progesterone Placebo	18 Years - 40 Years	TherapeuticsMD
Insulin Differences Between African-American and Caucasian Female Adolescents With Polycystic Ovary Syndrome (PCOS)	NCT02052479	Polycystic Ovar... PCOS	Frequently Samp...	12 Years - 18 Years	Nationwide Children's Hospital
Insulin Differences Between African-American and Caucasian Female Adolescents With Polycystic Ovary Syndrome (PCOS)	NCT02052479	Polycystic Ovar... PCOS	Frequently Samp...	12 Years - 18 Years	Nationwide Children's Hospital
Safety and Efficacy of PROMETRIUM® Capsules in Induction of Secretory Conversion	NCT00160199	Secondary Ameno...	PROMETRIUM® 300... PROMETRIUM® 400...	18 Years - 45 Years	Solvay Pharmaceuticals
A Phase 3, Randomized, Three-Cycle, Double-Blind, Placebo-Controlled Study to Evaluate Induction of Secretory Conversion of Endometrium and Withdrawal Bleeding for Secondary Amenorrhea	NCT02019589	Secondary Ameno...	Progesterone Placebo	18 Years - 40 Years	TherapeuticsMD

Spots Global Cancer Trial Database for secondary amenorrhea