AMIGOS: Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01044862
• 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), University of Texas (Other), University of Vermont (Other), Wayne State University (Other)
• Enrollment: 900
• Locations: 14
• Arms: 3
• Duration (Months): 45
• Patients Per Site: 64.3
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The objective of this application is to identify a pharmacologic agent which helps couples in whom the female partner ovulates regularly successfully obtain their goal of delivering a healthy child, whose use will result in low rates of multiple gestations. The central hypothesis is that, in infertile ovulatory women undergoing ovarian stimulation (OS) and intrauterine insemination (IUI), the use of aromatase inhibitors (AI) will stimulate the ovaries sufficiently to produce no reduction in the rate of pregnancy, while significantly reducing the numbers of multiple gestational pregnancies that result from stimulation with clomiphene citrate (CC) or follicle stimulating hormone (FSH). The rationale for the proposed research is that reduction of multiple pregnancy rates could significantly reduce maternal and neonatal morbidity and mortality, as well as the cost of healthcare for these individuals and society.

Condition or Disease	Intervention/Treatment	Phase
Pregnancy; Unexplained Infertility	Drug: Letrozole (aromatase inhibitor); Drug: Clomiphene Citrate; Drug: Follicle Stimulating Hormone (gonadotropin)	Phase 3

Detailed Description

Patient Population

The population will consist of 900 women up to and including women ≥18 to ≤40 years years of age (at time of randomization) desirous of conceiving who will be recruited over approximately a two year period from the Reproductive Medicine Network (RMN) clinical sites and possibly from the Specialized Cooperative Center Programs in Reproductive Research (SCCPIR) sites, through public notification programs.

Study Design

This will be a multi-center, prospective, partially blinded clinical trial of gonadotropins vs. clomiphene citrate vs. aromatase inhibitors. The randomization scheme will be coordinated through the data coordination center (DCC) and the randomization will be stratified by each participating site and within each site for ages 18-34 and 35-40.

Treatment

Patients will be randomized to receive either FSH, CC, or an AI according to randomization tables generated by a computer randomization program. Treatment assignments will be blocked by site and age group. Subjects randomized to pill treatment will receive medication in double blinded fashion, receiving one type of pill (overcoated CC or AI). Subjects randomized to injectable medication(FSH) will receive vials of medication.

Primary efficacy parameter

Multiple gestation rate following recruitment of multiple follicular development with an AI, as compared to CC and FSH.

Secondary efficacy parameters

Rate of pregnancy obtained, live birth rate, and time to pregnancy following administration of an aromatase inhibitor, as compared to CC and FSH as well as the live birth rate of multiple gestation pregnancies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 900 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Aromatase Inhibitors (AI) A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.	Drug: Letrozole (aromatase inhibitor); A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.
Active Comparator: Clomiphene Citrate (CC) CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.	Drug: Clomiphene Citrate; CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.
Active Comparator: Follicle Stimulating Hormone (FSH) A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.	Drug: Follicle Stimulating Hormone (gonadotropin); A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.

Outcome Measures

Primary Outcome Measures

1. Multiple Gestation Rate Following Recruitment of Multiple Follicular Development With an AI, as Compared to CC and FSH. [Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks]

Secondary Outcome Measures

1. Rate of Pregnancy Obtained [Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks]

2. Time to Pregnancy [Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks]

3. Live Birth Rate [Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Women ≥18 to ≤40 years of age, with one or more years infertility history, desirous of conceiving, regularly ovulating (defined as 9 or more menses per year), at initiation of participation.

2. Normal uterine cavity and at least one open fallopian tube confirmed by hysterosalpingography (HSG), sonohysterography, or laparoscopy/hysteroscopy in the last three years preceding enrollment into the study. 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.

3. Evidence of ovarian function/reserve as assessed by day 3 (+/-2 days) FSH ≤12 IU/L within one year prior to study initiation.

4. Normal or corrected thyroid function within one year of study initiation.

5. Normal prolactin level within one year of study initiation.

6. In general good health, not taking any medications which could interfere with the study (e.g., FSH, insulin sensitizers).

7. Ability to have inseminations following hCG administration.

8. Male partner with total motile sperm in the ejaculate of at least 5 million sperm, within one year of study initiation.

Exclusion Criteria:

1. Currently pregnant or successful pregnancies within 12 months of initiating participation. Clinical intrauterine miscarriages prior to initiating participation, within ASRM guidelines: subjects over 35 must wait six months, while subjects under 35 must wait 12 months. No exclusion for biochemical pregnancies.

2. Undiagnosed abnormal uterine bleeding.

3. Suspicious ovarian mass.

4. 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 when the implants are still in place. A one-month washout will be required for patients on oral cyclic progestins.

5. Known 21-hydroxylase deficiency or other enzyme defect causing congenital adrenal hyperplasia.

6. Type I or Type II diabetes mellitus, or if receiving antidiabetic medications.

7. Known significant anemia (Hemoglobin <10 g/dL).

8. History of deep venous thrombosis, pulmonary embolus, or cerebrovascular event.

9. Known heart disease (New York Heart Association Class II or higher).

10. Known Liver disease (defined as AST or ALT>2 times normal, or total bilirubin >2.5 mg/dL).

11. Known Renal disease (defined as BUN >30 mg/dL or serum creatinine > 1.4 mg/dL).

12. History of, or suspected cervical carcinoma, endometrial carcinoma or breast carcinoma.

13. History of alcohol abuse (defined as >14 drinks/week) or binge drinking of ≥ 6 drinks at one time).

14. Known Cushing's disease.

15. Known or suspected adrenal or ovarian androgen secreting tumors.

16. Allergy or contraindication to the treatment medications: AI, gonadotropins, CC or hCG.

17. Couples with previous sterilization procedures (e.g. vasectomy, tubal ligation) which have been reversed.

18. 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.

19. 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.

20. Known moderate or severe endometriosis

21. Known polycystic ovarian syndrome as evidenced by anovulation or oligoovulation, hirsutism and/or elevated testosterone levels, and ovarian morphology on ultrasound examination.

22. Donated semen.

23. Couples in which either partner is legally married to someone else.

24. Medical conditions that are contraindications to pregnancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Birmingham	Birmingham	Alabama	United States	35249-7333
2	University of California, San Francisco	San Francisco	California	United States	94115
3	Stanford University Medical Center	Stanford	California	United States	94305-5317
4	University of Colorado	Aurora	Colorado	United States	80045
5	Yale University	New Haven	Connecticut	United States	06511
6	University of Michigan	Ann Arbor	Michigan	United States	48108
7	Wayne State University	Detroit	Michigan	United States	48201
8	University of Medicine and Dentistry of New Jersey	Newark	New Jersey	United States	07601
9	Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
10	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
11	Pennsylvania State University College of Medicine	Hershey	Pennsylvania	United States	17033
12	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
13	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78207
14	University of Vermont	Burlington	Vermont	United States	05405

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
• University of Texas
• 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: Michael Diamond, MD, Wayne State University
• Study Director: Richard Legro, MD, Pennsylvania State University College of Medicine
• Study Director: William Schlaff, MD, University of Colorado Denver Health Science Center
• Study Director: Gregory Christman, MD, University of Michigan
• Study Director: Christos Coutifaris, MD, University of Pennsylvania
• 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: Heping Zhang, PhD, Yale University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Reproductive Medicine Network Homepage

Publications

None provided.

• Responsible Party: Heping Zhang, Principal Investigator, Yale University
• ClinicalTrials.gov Identifier: NCT01044862
• Other Study ID Numbers: RMN-AMIGOS; 3U10HD055925-02S1; 5U10HD055925; 3U10HD039005-08S1; 5U10HD039005
• First Posted: Jan 8, 2010
• Last Update Posted: Feb 2, 2015
• Last Verified: Jan 1, 2015

• Keywords provided by Heping Zhang, Principal Investigator, Yale University: Pregnancy; Infertility; Ovarian stimulation; Aromatase inhibitors; Follicle Stimulating Hormone
• Additional relevant MeSH terms: Infertility; Letrozole; Clomiphene; Enclomiphene; Zuclomiphene; Hormones; Follicle Stimulating Hormone; Aromatase Inhibitors

Study Results

Participant Flow

Arm/Group Title	Aromatase Inhibitors (AI)	Clomiphene Citrate (CC)	Follicle Stimulating Hormone (FSH)
Arm/Group Description	A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained. Letrozole (aromatase inhibitor): A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.	CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d. Clomiphene Citrate: CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.	A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used. Follicle Stimulating Hormone (gonadotropin): A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.
Period Title: Overall Study
STARTED	299	300	301
COMPLETED	246	251	249
NOT COMPLETED	53	49	52

Baseline Characteristics

Arm/Group Title	Aromatase Inhibitors (AI)	Clomiphene Citrate (CC)	Follicle Stimulating Hormone (FSH)	Total
Arm/Group Description	A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained. Letrozole (aromatase inhibitor): A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.	CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d. Clomiphene Citrate: CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.	A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used. Follicle Stimulating Hormone (gonadotropin): A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.	Total of all reporting groups
Overall Participants	299	300	301	900
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.2 (4.3)	32.0 (4.6)	32.2 (4.1)	32.2 (4.4)
Sex: Female, Male (Count of Participants)
Female	299 100%	300 100%	301 100%	900 100%
Male	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	299 100%	300 100%	301 100%	900 100%

Outcome Measures

1. Primary Outcome

Title	Multiple Gestation Rate Following Recruitment of Multiple Follicular Development With an AI, as Compared to CC and FSH.
Time Frame	Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aromatase Inhibitors (AI)	Clomiphene Citrate (CC)	Follicle Stimulating Hormone (FSH)
Arm/Group Description	A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained. Letrozole (aromatase inhibitor): A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.	CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d. Clomiphene Citrate: CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.	A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used. Follicle Stimulating Hormone (gonadotropin): A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.
Measure Participants	85	106	140
Number [number of multiples]	9	8	34

2. Secondary Outcome

Title	Rate of Pregnancy Obtained
Time Frame	Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aromatase Inhibitors (AI)	Clomiphene Citrate (CC)	Follicle Stimulating Hormone (FSH)
Arm/Group Description	A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained. Letrozole (aromatase inhibitor): A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.	CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d. Clomiphene Citrate: CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.	A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used. Follicle Stimulating Hormone (gonadotropin): A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.
Measure Participants	299	300	301
Number [participants]	85 28.4%	106 35.3%	140 46.5%

3. Secondary Outcome

Title	Time to Pregnancy
Time Frame	Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aromatase Inhibitors (AI)	Clomiphene Citrate (CC)	Follicle Stimulating Hormone (FSH)
Arm/Group Description	A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained. Letrozole (aromatase inhibitor): A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.	CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d. Clomiphene Citrate: CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.	A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used. Follicle Stimulating Hormone (gonadotropin): A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.
Measure Participants	299	300	301
Mean (Standard Deviation) [days]	67.2 (55.6)	67.4 (49.8)	62.3 (43.8)

4. Secondary Outcome

Title	Live Birth Rate
Time Frame	Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aromatase Inhibitors (AI)	Clomiphene Citrate (CC)	Follicle Stimulating Hormone (FSH)
Arm/Group Description	A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained. Letrozole (aromatase inhibitor): A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.	CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d. Clomiphene Citrate: CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.	A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used. Follicle Stimulating Hormone (gonadotropin): A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.
Measure Participants	299	300	301
Number [participants]	56 18.7%	70 23.3%	97 32.2%

Adverse Events

Adverse Event Reporting Description	The Numbers of Participants at Risk are different from the numbers provided in the Participant Flow module as not all subjects who were analyzed were administered study drug and therefore not all subjects were at risk for Adverse Events. Intent-to-treat analysis kept them in the study, but they had no AE risk.
Arm/Group Title	Aromatase Inhibitors (AI)		Clomiphene Citrate (CC)		Follicle Stimulating Hormone (FSH)
Arm/Group Description	A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained. Letrozole (aromatase inhibitor): A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.		CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d. Clomiphene Citrate: CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.		A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used. Follicle Stimulating Hormone (gonadotropin): A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.
All Cause Mortality
	Aromatase Inhibitors (AI)		Clomiphene Citrate (CC)		Follicle Stimulating Hormone (FSH)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Aromatase Inhibitors (AI)		Clomiphene Citrate (CC)		Follicle Stimulating Hormone (FSH)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/291 (3.8%)		12/298 (4%)		25/297 (8.4%)
Cardiac disorders
Hypertension	1/291 (0.3%)	1	1/298 (0.3%)	1	0/297 (0%)	0
Congenital, familial and genetic disorders
Congenital anomaly	2/291 (0.7%)	2	3/298 (1%)	3	3/297 (1%)	3
Gastrointestinal disorders
Cholecystitis	0/291 (0%)	0	0/298 (0%)	0	1/297 (0.3%)	1
Hyperemesis	0/291 (0%)	0	0/298 (0%)	0	2/297 (0.7%)	2
General disorders
Hospitalization for pain	0/291 (0%)	0	0/298 (0%)	0	1/297 (0.3%)	2
Neonatal Death	1/291 (0.3%)	1	0/298 (0%)	0	0/297 (0%)	0
Infections and infestations
Acute viral illness	0/291 (0%)	0	0/298 (0%)	0	1/297 (0.3%)	1
Injury, poisoning and procedural complications
Hemorrhagic Hematoma	1/291 (0.3%)	1	0/298 (0%)	0	0/297 (0%)	0
Pregnancy, puerperium and perinatal conditions
Pregnancy of Unknown Location	0/291 (0%)	0	2/298 (0.7%)	2	1/297 (0.3%)	1
Severe pre-eclampsia; HELLP syndrome, preterm labor	0/291 (0%)	0	1/298 (0.3%)	1	0/297 (0%)	0
Emergency C-section due to eclampsia	0/291 (0%)	0	0/298 (0%)	0	1/297 (0.3%)	1
Ectopic pregnancy	5/291 (1.7%)	5	5/298 (1.7%)	5	11/297 (3.7%)	11
Renal and urinary disorders
Presumed Pyelonephritis	0/291 (0%)	0	0/298 (0%)	0	1/297 (0.3%)	1
Reproductive system and breast disorders
Pyosalpinx Post IUI	0/291 (0%)	0	0/298 (0%)	0	1/297 (0.3%)	1
Ovarian Hyperstimulation Syndrome	0/291 (0%)	0	0/298 (0%)	0	1/297 (0.3%)	1
Pain due to ovarian enlargement	0/291 (0%)	0	0/298 (0%)	0	1/297 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Hospitalization due to shorness of breath; pulmonary edema	1/291 (0.3%)	2	0/298 (0%)	0	0/297 (0%)	0
Other (Not Including Serious) Adverse Events
	Aromatase Inhibitors (AI)		Clomiphene Citrate (CC)		Follicle Stimulating Hormone (FSH)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	218/291 (74.9%)		214/298 (71.8%)		217/297 (73.1%)
Endocrine disorders
Hot Flashes	49/291 (16.8%)	49	92/298 (30.9%)	92	25/297 (8.4%)	25
Gastrointestinal disorders
Abdominal Bloating	54/291 (18.6%)	54	50/298 (16.8%)	50	81/297 (27.3%)	81
Constipation	8/291 (2.7%)	8	28/298 (9.4%)	28	6/297 (2%)	6
General disorders
Injection Site Reaction	9/291 (3.1%)	9	6/298 (2%)	6	32/297 (10.8%)	32
Musculoskeletal and connective tissue disorders
Joint/Limb pain	17/291 (5.8%)	17	8/298 (2.7%)	8	5/297 (1.7%)	5
Nervous system disorders
Headache	122/291 (41.9%)	122	104/298 (34.9%)	104	89/297 (30%)	89
Reproductive system and breast disorders
Breast Pain	26/291 (8.9%)	26	19/298 (6.4%)	19	65/297 (21.9%)	65

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.