Clinical trial NCT01044862: Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation
Official title: Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pregnancy
Unexplained Infertility
Keywords: Pregnancy
Infertility
Ovarian stimulation
Aromatase inhibitors
Follicle Stimulating Hormone
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Penn State University
name: University of Colorado, Denver
name: University of Michigan
name: University of Pennsylvania
name: University of Texas
name: University of Vermont
name: Wayne State University
First posted: 2010-01-08
Enrollment: 900
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Multiple Gestation Rate Following Recruitment of Multiple Follicular Development With an AI, as Compared to CC and FSH.
timeFrame: Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks
Secondary outcomes:
measure: Rate of Pregnancy Obtained
timeFrame: Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks
measure: Time to Pregnancy
timeFrame: Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks
measure: Live Birth Rate
timeFrame: Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Newark
country: United States
facility: University of Medicine and Dentistry of New Jersey
state: New Jersey
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Hershey
country: United States
facility: Pennsylvania State University College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Esther Eisenberg, MD, MPH
role: STUDY_DIRECTOR
affiliation: Albert Einstein College of Medicine
name: Nanette Santoro, MD
role: STUDY_CHAIR
affiliation: Wayne State University
name: Michael Diamond, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pennsylvania State University College of Medicine
name: Richard Legro, MD
role: STUDY_DIRECTOR
affiliation: University of Colorado Denver Health Science Center
name: William Schlaff, MD
role: STUDY_DIRECTOR
affiliation: University of Michigan
name: Gregory Christman, MD
role: STUDY_DIRECTOR
affiliation: University of Pennsylvania
name: Christos Coutifaris, MD
role: STUDY_DIRECTOR
affiliation: The University of Texas Health Science Center at San Antonio
name: Robert Brzyski, MD, PhD
role: STUDY_DIRECTOR
affiliation: University of Vermont
name: Peter Casson, MD
role: STUDY_DIRECTOR
affiliation: Yale University
name: Heping Zhang, PhD
role: STUDY_DIRECTOR
References:
citation: Gavrizi SZ, Arya S, Peck JD, Knudtson JF, Diamond MP, Wild RA, Hansen KR. High-sensitivity C-reactive protein levels and pregnancy outcomes in women with unexplained infertility after ovarian stimulation with intrauterine insemination in a multicenter trial. F S Rep. 2022 Jan 11;3(1):57-62. doi: 10.1016/j.xfre.2022.01.001. eCollection 2022 Mar.
citation: Souter I, Sun F, Zhang H, Diamond MP, Legro RS, Wild RA, Hansen KR, Santoro N; Eunice Kennedy Schriver National Institute of Child Health and Human Development Reproductive Medicine Network. A personalized medicine approach to ovulation induction/ovarian stimulation: development of a predictive model and online calculator from level-I evidence. Fertil Steril. 2022 Feb;117(2):408-418. doi: 10.1016/j.fertnstert.2021.10.024.
citation: Eisenberg E, Legro RS, Diamond MP, Huang H, O'Brien LM, Smith YR, Coutifaris C, Hansen KR, Santoro N, Zhang H. Sleep Habits of Women With Infertility. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4414-e4426. doi: 10.1210/clinem/dgab474.
citation: Engmann L, Sun F, Legro RS, Diamond MP, Zhang H, Santoro N; Reproductive Medicine Network. Factors associated with study protocol adherence and bio banking participation in reproductive medicine clinical trials and their relationship to live birth. Hum Reprod. 2020 Dec 1;35(12):2819-2831. doi: 10.1093/humrep/deaa232.
citation: Quaas AM, Gavrizi SZ, Peck JD, Diamond MP, Legro RS, Robinson RD, Casson P, Christman GM, Zhang H, Hansen KR; Eunice Kennedy Shriver National Institute of Child Health and Human Development Reproductive Medicine Network. Endometrial thickness after ovarian stimulation with gonadotropin, clomiphene, or letrozole for unexplained infertility, and association with treatment outcomes. Fertil Steril. 2021 Jan;115(1):213-220. doi: 10.1016/j.fertnstert.2020.07.030. Epub 2020 Sep 21.
citation: Kaing A, Jaswa EA, Diamond MP, Legro RS, Cedars MI, Huddleston HG. Highly elevated level of antimullerian hormone associated with preterm delivery in polycystic ovary syndrome patients who underwent ovulation induction. Fertil Steril. 2021 Feb;115(2):438-446. doi: 10.1016/j.fertnstert.2020.06.015. Epub 2020 Sep 1.
citation: Wang ET, Diamond MP, Alvero R, Casson P, Christman GM, Coutifaris C, Hansen KR, Sun F, Legro RS, Robinson RD, Usadi RS, Pisarska MD, Santoro NF, Zhang H; National Institute of Child Health and Human Development (NICHD) Reproductive Medicine Network. Androgenicity and fertility treatment in women with unexplained infertility. Fertil Steril. 2020 Mar;113(3):636-641. doi: 10.1016/j.fertnstert.2019.10.034.
citation: Trussell JC, Coward RM, Santoro N, Stetter C, Kunselman A, Diamond MP, Hansen KR, Krawetz SA, Legro RS, Heisenleder D, Smith J, Steiner A, Wild R, Casson P, Coutifaris C, Alvero RR, Robinson RB, Christman G, Patrizio P, Zhang H, Lindgren MC; Reproductive Medicine Network. Association between testosterone, semen parameters, and live birth in men with unexplained infertility in an intrauterine insemination population. Fertil Steril. 2019 Jun;111(6):1129-1134. doi: 10.1016/j.fertnstert.2019.01.034. Epub 2019 Apr 12.
citation: Barrett ES, Vitek W, Mbowe O, Thurston SW, Legro RS, Alvero R, Baker V, Bates GW, Casson P, Coutifaris C, Eisenberg E, Hansen K, Krawetz S, Robinson R, Rosen M, Usadi R, Zhang H, Santoro N, Diamond M. Allostatic load, a measure of chronic physiological stress, is associated with pregnancy outcomes, but not fertility, among women with unexplained infertility. Hum Reprod. 2018 Sep 1;33(9):1757-1766. doi: 10.1093/humrep/dey261.
citation: Butts SF, Seifer DB, Koelper N, Senapati S, Sammel MD, Hoofnagle AN, Kelly A, Krawetz SA, Santoro N, Zhang H, Diamond MP, Legro RS; Eunice Kennedy Shriver National Institute of Child Health and Human Development Reproductive Medicine Network. Vitamin D Deficiency Is Associated With Poor Ovarian Stimulation Outcome in PCOS but Not Unexplained Infertility. J Clin Endocrinol Metab. 2019 Feb 1;104(2):369-378. doi: 10.1210/jc.2018-00750.
citation: Evans-Hoeker EA, Eisenberg E, Diamond MP, Legro RS, Alvero R, Coutifaris C, Casson PR, Christman GM, Hansen KR, Zhang H, Santoro N, Steiner AZ; Reproductive Medicine Network. Major depression, antidepressant use, and male and female fertility. Fertil Steril. 2018 May;109(5):879-887. doi: 10.1016/j.fertnstert.2018.01.029.
citation: Hansen KR, Eisenberg E, Baker V, Hill MJ, Chen S, Talken S, Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Santoro N, Zhang H, Wild RA; NICHD Reproductive Medicine Network. Midluteal Progesterone: A Marker of Treatment Outcomes in Couples With Unexplained Infertility. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2743-2751. doi: 10.1210/jc.2018-00642.
citation: Seungdamrong A, Steiner AZ, Gracia CR, Legro RS, Diamond MP, Coutifaris C, Schlaff WD, Casson P, Christman GM, Robinson RD, Huang H, Alvero R, Hansen KR, Jin S, Eisenberg E, Zhang H, Santoro N; Eunice Kennedy Shriver National Institute of Child Health and Human Development Reproductive Medicine Network. Preconceptional antithyroid peroxidase antibodies, but not thyroid-stimulating hormone, are associated with decreased live birth rates in infertile women. Fertil Steril. 2017 Oct 25:S0015-0282(17)31748-X. doi: 10.1016/j.fertnstert.2017.08.026. Online ahead of print.
citation: Styer AK, Jin S, Liu D, Wang B, Polotsky AJ, Christianson MS, Vitek W, Engmann L, Hansen K, Wild R, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Christy A, Diamond MP, Eisenberg E, Zhang H, Santoro N; National Institute of Child Health and Human Development Reproductive Medicine Network. Association of uterine fibroids and pregnancy outcomes after ovarian stimulation-intrauterine insemination for unexplained infertility. Fertil Steril. 2017 Mar;107(3):756-762.e3. doi: 10.1016/j.fertnstert.2016.12.012. Epub 2017 Jan 12.
citation: Santoro N, Eisenberg E, Trussell JC, Craig LB, Gracia C, Huang H, Alvero R, Casson P, Christman G, Coutifaris C, Diamond M, Jin S, Legro RS, Robinson RD, Schlaff WD, Zhang H; Reproductive Medicine Network Investigators. Fertility-related quality of life from two RCT cohorts with infertility: unexplained infertility and polycystic ovary syndrome. Hum Reprod. 2016 Oct;31(10):2268-79. doi: 10.1093/humrep/dew175. Epub 2016 Jul 7.
citation: Hansen KR, He AL, Styer AK, Wild RA, Butts S, Engmann L, Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Huang H, Santoro N, Eisenberg E, Zhang H; Eunice Kennedy Shriver National Institute of Child Health and Human Development Reproductive Medicine Network. Predictors of pregnancy and live-birth in couples with unexplained infertility after ovarian stimulation-intrauterine insemination. Fertil Steril. 2016 Jun;105(6):1575-1583.e2. doi: 10.1016/j.fertnstert.2016.02.020. Epub 2016 Mar 3.
citation: Steiner AZ, Diamond MP, Legro RS, Schlaff WD, Barnhart KT, Casson PR, Christman GM, Alvero R, Hansen KR, Geisler WM, Thomas T, Santoro N, Zhang H, Eisenberg E; Reproductive Medicine Network. Chlamydia trachomatis immunoglobulin G3 seropositivity is a predictor of reproductive outcomes in infertile women with patent fallopian tubes. Fertil Steril. 2015 Dec;104(6):1522-6. doi: 10.1016/j.fertnstert.2015.08.022. Epub 2015 Sep 25.
citation: Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Ager J, Huang H, Hansen KR, Baker V, Usadi R, Seungdamrong A, Bates GW, Rosen RM, Haisenleder D, Krawetz SA, Barnhart K, Trussell JC, Ohl D, Jin Y, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive Medicine Network. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med. 2015 Sep 24;373(13):1230-40. doi: 10.1056/NEJMoa1414827.
citation: Kuang H, Jin S, Thomas T, Engmann L, Hansen KR, Coutifaris C, Casson P, Christman G, Alvero R, Santoro N, Eisenberg E, Diamond MP, Legro RS, Zhang H; Reproductive Medicine Network. Predictors of participant retention in infertility treatment trials. Fertil Steril. 2015 Nov;104(5):1236-43.e1-2. doi: 10.1016/j.fertnstert.2015.08.001. Epub 2015 Sep 3.
citation: Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, Christman GM, Ager J, Huang H, Hansen KR, Baker V, Usadi R, Seungdamrong A, Bates GW, Rosen RM, Haisonleder D, Krawetz SA, Barnhart K, Trussell JC, Jin Y, Santoro N, Eisenberg E, Zhang H; National Institute of Child Health and Human Development (NICHD) Reproductive Medicine Network. Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics. Fertil Steril. 2015 Apr;103(4):962-973.e4. doi: 10.1016/j.fertnstert.2014.12.130. Epub 2015 Feb 20.