Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation

Phase 3

Completed

• Conditions: Pregnancy; Unexplained Infertility
• Interventions: Drug: Follicle Stimulating Hormone (gonadotropin); Drug: Letrozole (aromatase inhibitor); Drug: Clomiphene Citrate

• Registration Number: NCT01044862
• Lead Sponsor: Yale University

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.

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 Timeline

• Study First Submitted: 2010-01-07
• Study First Submitted QC: 2010-01-07
• Study First Posted: 2010-01-08
• Study Start: 2010-06
• Primary Completion: 2013-10
• Study Completion: 2014-03
• Status Verified: 2015-01
• Results First Submitted: 2015-01-06
• Results First Submitted QC: 2015-01-22
• Last Update Submitted: 2015-01-22
• Results First Posted: 2015-02-02
• Last Update Posted: 2015-02-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 900

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Follicle Stimulating Hormone (FSH)	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.
Aromatase Inhibitors (AI)	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.
Clomiphene Citrate (CC)	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.

Primary Outcome Measures

Name	Time	Method
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

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

Trial Locations

Locations (14)

University of Texas Health Science Center at San Antonio; 🇺🇸 San Antonio, Texas, United States

University of Colorado; 🇺🇸 Aurora, Colorado, United States

University of Alabama Birmingham; 🇺🇸 Birmingham, Alabama, United States

Wayne State University; 🇺🇸 Detroit, Michigan, United States

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

Stanford University Medical Center; 🇺🇸 Stanford, California, United States

Yale University; 🇺🇸 New Haven, Connecticut, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

University of Medicine and Dentistry of New Jersey; 🇺🇸 Newark, New Jersey, United States

Carolinas Medical Center; 🇺🇸 Charlotte, North Carolina, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Pennsylvania State University College of Medicine; 🇺🇸 Hershey, Pennsylvania, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

University of Vermont; 🇺🇸 Burlington, Vermont, United States