Pregnancy, Unexplained Infertility
Conditions
Keywords
Pregnancy, Infertility, Ovarian stimulation, Aromatase inhibitors, Follicle Stimulating Hormone
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.
Interventions
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.
DRUGClomiphene 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.
DRUGFollicle 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.
Sponsors
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
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 299 |
| 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.
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. | 300 |
| 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.
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. | 301 |
| Total | 900 |
Baseline characteristics
| Characteristic | Aromatase Inhibitors (AI) | Clomiphene Citrate (CC) | Follicle Stimulating Hormone (FSH) | Total |
|---|---|---|---|---|
| Age, Continuous | 32.2 years STANDARD_DEVIATION 4.3 | 32.0 years STANDARD_DEVIATION 4.6 | 32.2 years STANDARD_DEVIATION 4.1 | 32.2 years STANDARD_DEVIATION 4.4 |
| Region of Enrollment United States | 299 participants | 300 participants | 301 participants | 900 participants |
| Sex: Female, Male Female | 299 Participants | 300 Participants | 301 Participants | 900 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 218 / 291 | 214 / 298 | 217 / 297 |
| serious Total, serious adverse events | 11 / 291 | 12 / 298 | 25 / 297 |
Outcome results
Primary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aromatase Inhibitors (AI) | Multiple Gestation Rate Following Recruitment of Multiple Follicular Development With an AI, as Compared to CC and FSH. | 9 number of multiples |
| Clomiphene Citrate (CC) | Multiple Gestation Rate Following Recruitment of Multiple Follicular Development With an AI, as Compared to CC and FSH. | 8 number of multiples |
| Follicle Stimulating Hormone (FSH) | Multiple Gestation Rate Following Recruitment of Multiple Follicular Development With an AI, as Compared to CC and FSH. | 34 number of multiples |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aromatase Inhibitors (AI) | Live Birth Rate | 56 participants |
| Clomiphene Citrate (CC) | Live Birth Rate | 70 participants |
| Follicle Stimulating Hormone (FSH) | Live Birth Rate | 97 participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aromatase Inhibitors (AI) | Rate of Pregnancy Obtained | 85 participants |
| Clomiphene Citrate (CC) | Rate of Pregnancy Obtained | 106 participants |
| Follicle Stimulating Hormone (FSH) | Rate of Pregnancy Obtained | 140 participants |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitors (AI) | Time to Pregnancy | 67.2 days | Standard Deviation 55.6 |
| Clomiphene Citrate (CC) | Time to Pregnancy | 67.4 days | Standard Deviation 49.8 |
| Follicle Stimulating Hormone (FSH) | Time to Pregnancy | 62.3 days | Standard Deviation 43.8 |