PPCOSII: Pregnancy in Polycystic Ovary Syndrome II

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00719186
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), Penn State University (Other), University of Colorado, Denver (Other), University of Michigan (Other), University of Pennsylvania (Other), The University of Texas Health Science Center at San Antonio (Other), University of Vermont (Other), Wayne State University (Other)
• Enrollment: 750
• Locations: 12
• Arms: 2
• Duration (Months): 50.9
• Patients Per Site: 62.5
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The primary research hypothesis is that ovulation induction with an aromatase inhibitor (letrozole) is more likely to result in live birth than ovulation induction with a selective estrogen receptor modulator (clomiphene citrate) in infertile women with PCOS. A safety hypothesis will also be incorporated into the primary research hypothesis in which we hypothesize both treatments are equally safe for mother and child.

Secondary research hypotheses include:

1. Treatment with letrozole is more likely to result in singleton pregnancy compared to treatment with clomiphene citrate. Singleton pregnancy is defined as presence of a single intrauterine gestational sac with a single fetal pole and observable heart motion.

2. Treatment with letrozole will less likely result in a first trimester intrauterine fetal demise than treatment with clomiphene citrate. A first trimester IUFD is defined as a pregnancy that ends before 13 weeks gestation.

3. Treatment with letrozole is more likely to result in ovulation (increased ovulation rate) compared to treatment with clomiphene citrate. Ovulation is defined as a midluteal progesterone level ≥ 3 ng/mL.

4. The shortest time to pregnancy will be with letrozole.

5. Age, body mass index, SHBG, testosterone, LH, Anti-Mullerian Hormone (AMH), and degree of hirsutism and acne will be significant predictors of ovulation and conception regardless of treatment.

6. Improvement in SHBG, testosterone, AMH, and LH levels will be significant predictors of ovulation and conception regardless of treatment.

7. DNA polymorphisms in estrogen action genes will predict response to study drug.

8. Quality of Life will be better on letrozole than clomiphene.

9. Letrozole will be more cost effective at achieving singleton pregnancies than clomiphene.

Condition or Disease	Intervention/Treatment	Phase
Pregnancy; Polycystic Ovary Syndrome	Drug: Clomiphene citrate; Drug: Letrozole	Phase 3

Detailed Description

Preliminary data are promising for the use of letrozole to induce ovulation in infertile women with PCOS. However the true magnitude of the effect of letrozole is difficult to discern from prior studies. Therefore we intend to determine the safety and efficacy of letrozole, an aromatase inhibitor, compared to clomiphene citrate, a selective estrogen receptor modulator, in achieving live birth in infertile women with PCOS.

Treatment- After progestin withdrawal, 750 women will be equally randomized to two different treatment arms: A) clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), or B) letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks. Dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of clomiphene a day (x 5 days) or 7.5 mg of letrozole a day (x 5 days).

Statistical Analysis- The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms.

Anticipated time to completion- A total of 4 years will be required to complete the study after start up; 31 month enrollment period, 5 month treatment period, with 9 month additional observation to determine pregnancy outcomes. This will be accomplished by enrolling ~3.45 women with PCOS per center per month over the enrollment period (N = 7 RMN sites).

Study Design

• Study Type: Interventional
• Actual Enrollment: 750 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 20 Week Double-Blind Randomized Trial of Clomiphene Citrate and Letrozole for the Treatment of Infertility in Women With Polycystic Ovary Syndrome
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Drug: Clomiphene citrate; Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks; Other Names: Clomid Serophene
Active Comparator: B Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Drug: Letrozole; Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks; Other Names: Femara

Outcome Measures

Primary Outcome Measures

1. Live Birth [as few as 5 months, up to 16 months]

   The primary outcome measure is the occurrence of a live birth during the study period. Safety measures will be the number and type of reported adverse events in subjects and offspring.

Secondary Outcome Measures

1. Number of Pregnancy [as few as 5 months, up to 16 months]

2. Number of Ovulations [as few as 5 months, up to 16 months]

3. Number of Serious Adverse Events [as few as 5 months, up to 16 months]

4. Neonatal Complication Rate [September 2008 - December 2011]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Key Inclusion Criteria (Must have ovulatory dysfunction and either hyperandrogenism or PCO)

1. Chronic anovulation or oligomenorrhea: defined as spontaneous intermenstrual periods of ≥45 days or a total of ≤8 menses per year, or for women with suspected anovulatory bleeding, a midluteal serum progesterone level < 3 ng/mL is indicative of chronic anovulation. For women who have been on ovarian suppressive therapy or other confounding medication (i.e. insulin sensitizing agents) within the last year prior to the study, a history of ≤8 menses per year prior to the initiation of this prior therapy will qualify as evidence of oligomenorrhea. For women with more regular bleeding patterns, but who are suspected to be experiencing anovulatory bleeding, a midluteal progesterone level < 3ng/mL will be evidence of ovulatory dysfunction and qualify as anovulation. Undiagnosed persistent vaginal bleeding should be diagnosed and treated prior to enrollment.

2. Hyperandrogenism (either Hirsutism or Hyperandrogenemia) or Polycystic Ovaries on

Ultrasound:

1. Hirsutism is determined by a modified Ferriman-Gallwey Score >8 at screening exam (Hatch, Rosenfield et al. 1981 Aug 1). Subjects who have hirsutism do not need local or core labs documenting elevated androgen levels.

2. Hyperandrogenemia can be determined from local labs. Local cutoffs will be pre-determined by each site prior to study initiation. Hyperandrogenemia will be defined as an elevated total testosterone, or free androgen index (FAI)(in our lab at Penn State College of Medicine a total T > 50 ng/dL or a free androgen index >5) will allow entry into the study (Legro, Driscoll et al. 1998). The FAI is calculated from measurable values for total T and SHBG, as previously described (Miller, Rosner et al. 2004), using the following equation: (FAI = Total testosterone in nmol/L / SHBG in nmol/L) X 100. Outside lab values obtained within the last year documenting elevated T or FAI levels are sufficient to meet criteria of hyperandrogenemia.

3. Polycystic Ovaries on Ultrasound: We will use the revised Rotterdam criteria for diagnosing polycystic ovaries (Balen, Laven et al. 2003). PCO will be defined as either an ovary that contains 12 or more follicles measuring 2-9 mm in diameter, or an increased ovarian volume (> 10 cm3) on one ovary for entry into the study. If there is a follicle > 10 mm in diameter, the scan should be repeated at a time of ovarian quiescence in order to calculate volume and area if the subject does not otherwise qualify for the study. The presence of a single polycystic ovary (PCO), either by volume or morphology, is sufficient to provide the diagnosis.

Exclusion Criteria:

We will exclude subjects with medical conditions that represent contraindications to CC, aromatase inhibitors and/or pregnancy or who are unable to comply with the study procedures. We will exclude subjects with poorly controlled Type I or Type II diabetes; undiagnosed liver disease or dysfunction (based on serum liver enzyme testing); renal disease or abnormal serum renal function; significant anemia; history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident; uncontrolled hypertension, known symptomatic heart disease; history of or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma; undiagnosed vaginal bleeding, and use of other medications known to affect reproductive function or metabolism (e.g., OCP, GnRH agonists and antagonists, antiandrogens, gonadotropins, anti-obesity drugs, somatostatin, diazoxide, ACE inhibitors, and calcium channel blockers). As in PPCOS we will allow a 2 months washout period for subjects who desire to participate and discontinue exclusionary medications (most commonly OCP, but also possibly metformin), and a period of observation or treatment for correctable conditions.

Couple Inclusion Criteria

1. Sperm concentration of 14 million/mL in at least one ejaculate within the last year, with at least some motile sperm.

2. Ability to have regular intercourse during the ovulation induction phase of the study.

3. At least one patent tube and normal uterine cavity as determined by sonohysterogram, hysterosalpingogram, or hysteroscopy/laparoscopy within the last 3 years. An uncomplicated intrauterine non-IVF pregnancy and uncomplicated delivery and postpartum course resulting in live birth within the last three years will also serve as sufficient evidence of a patent tube and normal uterine cavity as long as the subject did not have, during the pregnancy or subsequently, risk factors for Asherman's syndrome or tubal disease or other disorder leading to an increased suspicion for intrauterine abnormality or tubal occlusion.

4. No previous sterilization procedures (vasectomy, tubal ligation) that have been reversed. The prior procedure may affect study outcomes.

Specific Exclusion Criteria

1. Current pregnancy.

2. Patients on oral contraceptives, depo-progestins, or hormonal implants (including Implanon). A two month washout period will be required prior to screening for patients on these agents. Longer washouts may be necessary for certain depot contraceptive forms or implants, especially where the implants are still in place. A one-month washout will be required for patients on oral cyclic progestins.

3. Patients with hyperprolactinemia (defined as two prolactin levels at least one week apart > 30 ng/mL or as determined by local normative values). The goal of eliminating patients with documented hyperprolactinemia is to decrease the heterogeneity of the PCOS population. These patients may be candidates for ovulation induction with alternate regimens (dopamine agonists). A normal level within the last year or on treatment is adequate for entry.

4. Patients with known 21-hydroxylase deficiency or other enzyme deficiency leading to the phenotype of congenital adrenal hyperplasia. 21-hydroxylase deficiency will be excluded in all patients by a fasting 17-hydroxyprogesterone (17-OHP) level <2 ng/mL (Azziz, Hincapie et al. 1999 Nov). If relevant, this level should be determined in the follicular phase, because the 17-hydroxyprogesterone level is likely to be elevated beyond this range if the patient is in the luteal phase of an infrequent ovulatory cycle. In the case of elevated fasting 17-OHP levels in the follicular phase, an ACTH stimulation test will be performed. A 1-hour stimulated value > 10 ng/mL will be an exclusion (Moran, Knochenhauer et al. 1998). As 21-hydroxylase deficiency is a congenital condition, any normal level in the past of 17-hydroxyprogesterone allows entry into this study.

5. Patients with menopausal levels of FSH (> 15 mIU/mL). A normal level within the last year is adequate for entry.

6. Patients with uncorrected thyroid disease (defined as TSH < 0.2 mIU/mL or >5.5 mIU/mL). A normal level within the last year is adequate for entry.

7. Patients diagnosed with Type I or Type II diabetes who are poorly controlled (defined as a glycohemoglobin level > 7.0%), or patients receiving antidiabetic medications such as insulin, thiazolidinediones, acarbose, or sulfonylureas likely to confound the effects of study medication; patients currently receiving metformin XR for a diagnosis of Type I or Type II diabetes or for PCOS are also specifically excluded.

8. Patients with liver disease defined as AST or ALT > 2 times normal or total bilirubin

2.5 mg/dL.

1. Patients with renal disease defined as BUN > 30 mg/dL or serum creatinine> 1.4 mg/dL.

2. Patients with significant anemia (Hemoglobin < 10 g/dL).

3. Patients with a history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident.

4. Patients with known heart disease that is likely to be exacerbated by pregnancy.

5. Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma. A normal Pap smear result within ACOG guidelines for Pap smear frequency will be required for women 21 and over.

6. Patients with a current history of alcohol abuse. Alcohol abuse is defined as > 14 drinks/week or binge drinking.

7. Patients enrolled simultaneously into other investigative studies that require medications, proscribe the study medications, limit intercourse, or otherwise prevent compliance with the protocol. Patients who anticipate taking longer than a one month break during the protocol should not be enrolled.

8. Patients taking other medications known to affect reproductive function or metabolism. These medications include oral contraceptives, GnRH agonists and antagonists, antiandrogens, gonadotropins, anti-obesity drugs, anti-diabetic drugs such as metformin and thiazolidinediones, somatostatin, diazoxide, ACE inhibitors, and calcium channel blockers. The washout period on all these medications will be two months and a list is found in the appendix.

9. Patients with a suspected adrenal or ovarian tumor secreting androgens.

10. Patients with suspected Cushing's syndrome.

11. Couples with previous sterilization procedures (vasectomy, tubal ligation) which have been reversed. The prior procedure may affect study outcomes, and patients with both a reversed sterilization procedure and PCOS are rare enough that exclusion should not adversely affect recruitment.

12. Subjects who have undergone a bariatric surgery procedure in the recent past (<12 months) and are in a period of acute weight loss or have been advised against pregnancy by their bariatric surgeon.

13. Patients with untreated poorly controlled hypertension defined as a systolic blood pressure ≥ 160 mm Hg or a diastolic ≥ 100 mm Hg obtained on two measures obtained at least 60 minutes apart.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Birmingham	Birmingham	Alabama	United States	35249-7333
2	Stanford University Medical Center	Stanford	California	United States	94305-5317
3	University of Colorado	Aurora	Colorado	United States	80045
4	Yale University	New Haven	Connecticut	United States	06511
5	University of Michigan	Ann Arbor	Michigan	United States	48109
6	Wayne State University	Detroit	Michigan	United States	48201
7	Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
8	Pennsylvania State University College of Medicine	Hershey	Pennsylvania	United States	17033
9	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
10	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
11	University of Vermont	Burlington	Vermont	United States	05405
12	Virginia Commonwealth University, School of Medicine	Richmond	Virginia	United States	23235

Sponsors and Collaborators

• Yale University
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Penn State University
• University of Colorado, Denver
• University of Michigan
• University of Pennsylvania
• The University of Texas Health Science Center at San Antonio
• University of Vermont
• Wayne State University

Investigators

• Study Director: Esther Eisenberg, MD, MPH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Study Chair: Nanette Santoro, MD, Albert Einstein College of Medicine
• Principal Investigator: Richard Legro, MD, Pennsylvania State University College of Medicine
• Study Director: Robert Brzyski, MD, PhD, The University of Texas Health Science Center at San Antonio
• Study Director: Peter Casson, MD, University of Vermont
• Study Director: Michael Diamond, MD, Wayne State University
• Study Director: Heping Zhang, PhD, Yale University
• Study Director: Gregory M Christman, MD, University of Michigan
• Study Director: Christos Coutifaris, MD, University of Pennsylvania
• Study Director: William D Schlaff, MD, University of Colorado Denver Health Science Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Heping Zhang, Principal Investigator, Yale University
• ClinicalTrials.gov Identifier: NCT00719186
• Other Study ID Numbers: RMN-PPCOSII
• First Posted: Jul 21, 2008
• Last Update Posted: Jun 14, 2018
• Last Verified: May 1, 2018

• Keywords provided by Heping Zhang, Principal Investigator, Yale University: Polycystic Ovary Syndrome; Infertility; Pregnancy; Women
• Additional relevant MeSH terms: Polycystic Ovary Syndrome; Syndrome; Letrozole; Clomiphene; Enclomiphene; Zuclomiphene

Study Results

Participant Flow

Arm/Group Title	Arm A: Clomiphene Citrate	Arm B: Letrozole
Arm/Group Description	Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Clomiphene citrate: Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Letrozole: Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
Period Title: Overall Study
STARTED	376	374
COMPLETED	376	374
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm A: Clomiphene Citrate	Arm B: Letrozole	Total
Arm/Group Description	Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Clomiphene citrate: Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Letrozole: Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Total of all reporting groups
Overall Participants	376	374	750
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.2 (4.0)	28.9 (4.5)	28.9 (4.3)
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	376 100%	374 100%	750 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	376 100%	374 100%	750 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	376 100%	374 100%	750 100%

Outcome Measures

1. Primary Outcome

Title	Live Birth
Description	The primary outcome measure is the occurrence of a live birth during the study period. Safety measures will be the number and type of reported adverse events in subjects and offspring.
Time Frame	as few as 5 months, up to 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Clomiphene Citrate	Arm B: Letrozole
Arm/Group Description	Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Clomiphene citrate: Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Letrozole: Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
Measure Participants	376	374
Count of Participants [Participants]	72 19.1%	103 27.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Clomiphene Citrate, Arm B: Letrozole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Number of Pregnancy
Time Frame	as few as 5 months, up to 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Clomiphene Citrate	Arm B: Letrozole
Arm/Group Description	Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Clomiphene citrate: Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Letrozole: Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
Measure Participants	376	374
Count of Participants [Participants]	103 27.4%	154 41.2%

3. Secondary Outcome

Title	Number of Ovulations
Time Frame	as few as 5 months, up to 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Clomiphene Citrate	Arm B: Letrozole
Arm/Group Description	Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Clomiphene citrate: Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Letrozole: Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
Measure Participants	376	374
Number [ovulations]	331	388

4. Secondary Outcome

Title	Number of Serious Adverse Events
Time Frame	as few as 5 months, up to 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Clomiphene Citrate	Arm B: Letrozole
Arm/Group Description	Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Clomiphene citrate: Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Letrozole: Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
Measure Participants	376	374
Number [events]	13	22

5. Secondary Outcome

Title	Neonatal Complication Rate
Time Frame	September 2008 - December 2011

Outcome Measure Data

Analysis Population Description

Neonatal complications reported per infant, an infant could have more than one complication.

Arm/Group Title	Arm A: Clomiphene Citrate	Arm B: Letrozole
Arm/Group Description	Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Clomiphene citrate: Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks	Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Letrozole: Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
Measure Participants	66	102
Neonatal jaundice	17 4.5%	27 7.2%
Neonatal respiratory distress syndrome	2 0.5%	7 1.9%
Neonatal hospitalization >3 days	4 1.1%	4 1.1%
Intrauterine growth restriction	1 0.3%	5 1.3%
Neonatal infectin	2 0.5%	2 0.5%
Minor birth defect	0 0%	1 0.3%
Other complication	4 1.1%	5 1.3%
Congenital anomaly	1 0.3%	4 1.1%
Neonatal death	2 0.5%	1 0.3%

Adverse Events

Time Frame	4 years
Arm/Group Title	Arm A: Clomiphene Citrate		Arm B: Letrozole
Arm/Group Description	Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Clomiphene citrate: Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks		Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks Letrozole: Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
All Cause Mortality
	Arm A: Clomiphene Citrate		Arm B: Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A: Clomiphene Citrate		Arm B: Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/376 (3.5%)		21/374 (5.6%)
Congenital, familial and genetic disorders
Congenital Anomaly	1/376 (0.3%)		4/374 (1.1%)
Gastrointestinal disorders
Appendectomy	0/376 (0%)		1/374 (0.3%)
General disorders
Hospitalization	3/376 (0.8%)		5/374 (1.3%)
Hepatobiliary disorders
cholecystectomy	1/376 (0.3%)		1/374 (0.3%)
Cholecystitis	0/376 (0%)		1/374 (0.3%)
Pregnancy, puerperium and perinatal conditions
Fetal Demise	1/376 (0.3%)		1/374 (0.3%)
Neonatal death	2/376 (0.5%)		1/374 (0.3%)
Renal and urinary disorders
Mid ureteral stone	0/376 (0%)		1/374 (0.3%)
Reproductive system and breast disorders
Ovarian torsion	1/376 (0.3%)		0/374 (0%)
Ectopic Pregnancy	3/376 (0.8%)		4/374 (1.1%)
Ruptured Corpus Luteum Cyst	0/376 (0%)		1/374 (0.3%)
Heterotopic Pregnancy	1/376 (0.3%)		0/374 (0%)
Pregnancy of Unknown Location	1/376 (0.3%)		1/374 (0.3%)
Skin and subcutaneous tissue disorders
Carcinoma of the Skin-stage 3	1/376 (0.3%)		0/374 (0%)
Other (Not Including Serious) Adverse Events
	Arm A: Clomiphene Citrate		Arm B: Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	283/355 (79.7%)		285/359 (79.4%)
Endocrine disorders
Hot flashes	117/355 (33%)		73/359 (20.3%)
Eye disorders
Blurred vision	4/355 (1.1%)		8/359 (2.2%)
Gastrointestinal disorders
Nausea	91/355 (25.6%)		110/359 (30.6%)
Dyspepsia	62/355 (17.5%)		45/359 (12.5%)
Abdominal bloating	42/355 (11.8%)		49/359 (13.6%)
Diarrhea	18/355 (5.1%)		24/359 (6.7%)
Vomiting	20/355 (5.6%)		21/359 (5.8%)
Constipation	20/355 (5.6%)		17/359 (4.7%)
General disorders
Fatigue	53/355 (14.9%)		78/359 (21.7%)
Chills	8/355 (2.3%)		4/359 (1.1%)
First Trimester other complication during pregnancy	8/355 (2.3%)		15/359 (4.2%)
Hepatobiliary disorders
Neonatal Jaundice	17/355 (4.8%)		27/359 (7.5%)
Infections and infestations
Upper respiratory infection	31/355 (8.7%)		38/359 (10.6%)
Flu like symptoms	18/355 (5.1%)		29/359 (8.1%)
Vaginal infection	16/355 (4.5%)		8/359 (2.2%)
Allergic rhinitis	12/355 (3.4%)		10/359 (2.8%)
fever	9/355 (2.5%)		13/359 (3.6%)
Urinary tract infection	10/355 (2.8%)		12/359 (3.3%)
Post-partum Infection	2/355 (0.6%)		7/359 (1.9%)
Musculoskeletal and connective tissue disorders
abdominal/pelvic pain	138/355 (38.9%)		146/359 (40.7%)
Back pain	55/355 (15.5%)		64/359 (17.8%)
Joint/limb pain	26/355 (7.3%)		33/359 (9.2%)
Myalgia	9/355 (2.5%)		10/359 (2.8%)
Nervous system disorders
Headache	170/355 (47.9%)		167/359 (46.5%)
Dizziness	27/355 (7.6%)		44/359 (12.3%)
Pregnancy, puerperium and perinatal conditions
Second Trimester Hyperemesis	5/355 (1.4%)		8/359 (2.2%)
Second Trimester Gestational Diabetes	13/355 (3.7%)		27/359 (7.5%)
Second Trimester Pre-eclampsia/ eclampsia	13/355 (3.7%)		18/359 (5%)
Second Trimester pretem labor	12/355 (3.4%)		14/359 (3.9%)
Second Trimester Premature rupture of membrane	7/355 (2%)		8/359 (2.2%)
Second Trimester Incompetant cervix	6/355 (1.7%)		8/359 (2.2%)
Post-partum hemorrhage	3/355 (0.8%)		8/359 (2.2%)
Psychiatric disorders
Agitation	37/355 (10.4%)		43/359 (12%)
Irritability	33/355 (9.3%)		33/359 (9.2%)
Insomnia	14/355 (3.9%)		12/359 (3.3%)
Depression	10/355 (2.8%)		6/359 (1.7%)
Renal and urinary disorders
Urinary frequency	8/355 (2.3%)		7/359 (1.9%)
Reproductive system and breast disorders
Breast pain	76/355 (21.4%)		76/359 (21.2%)
Dysmenorrhea	64/355 (18%)		60/359 (16.7%)
Abnormal vaginal bleeding	9/355 (2.5%)		18/359 (5%)
Vaginal discharge	4/355 (1.1%)		9/359 (2.5%)
Respiratory, thoracic and mediastinal disorders
Sinus complaints	4/355 (1.1%)		8/359 (2.2%)
Neonatal respiratory distress syndrome	2/355 (0.6%)		7/359 (1.9%)
Skin and subcutaneous tissue disorders
Acne/ oily skin	24/355 (6.8%)		16/359 (4.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.