Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation

NCT01044862 | Completed Phase 3 Results DMC

• 5 other identifiers: RMN-AMIGOS3U10HD055925-02S15U10HD0559253U10HD039005-08S15U10HD039005
• Study Type: interventional
• Target: 900
• Locations: 1 country
• Sites: 14

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.

Conditions

Pregnancy; Unexplained Infertility

Keywords

Pregnancy; Infertility; Ovarian stimulation; Aromatase inhibitors; Follicle Stimulating Hormone

Outcome Measures

Primary Outcomes (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 Outcomes (3)

• 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

• Live Birth Rate

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

Study Arms (3)

Aromatase Inhibitors (AI)

ACTIVE COMPARATOR

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)

Clomiphene Citrate (CC)

ACTIVE COMPARATOR

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

Follicle Stimulating Hormone (FSH)

ACTIVE COMPARATOR

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)

Interventions

Letrozole (aromatase inhibitor) DRUG

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.

Aromatase Inhibitors (AI)

Clomiphene Citrate DRUG

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)

Follicle Stimulating Hormone (gonadotropin) DRUG

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 (FSH)

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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.
• Evidence of ovarian function/reserve as assessed by day 3 (+/-2 days) FSH ≤12 IU/L within one year prior to study initiation.
• Normal or corrected thyroid function within one year of study initiation.
• Normal prolactin level within one year of study initiation.
• In general good health, not taking any medications which could interfere with the study (e.g., FSH, insulin sensitizers).
• Ability to have inseminations following hCG administration.
• Male partner with total motile sperm in the ejaculate of at least 5 million sperm, within one year of study initiation.

You may not qualify if:

• Undiagnosed abnormal uterine bleeding.
• Suspicious ovarian mass.
• 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.
• Known 21-hydroxylase deficiency or other enzyme defect causing congenital adrenal hyperplasia.
• Type I or Type II diabetes mellitus, or if receiving antidiabetic medications.
• Known significant anemia (Hemoglobin \<10 g/dL).
• History of deep venous thrombosis, pulmonary embolus, or cerebrovascular event.
• Known heart disease (New York Heart Association Class II or higher).
• Known Liver disease (defined as AST or ALT\>2 times normal, or total bilirubin \>2.5 mg/dL).
• Known Renal disease (defined as BUN \>30 mg/dL or serum creatinine \> 1.4 mg/dL).
• History of, or suspected cervical carcinoma, endometrial carcinoma or breast carcinoma.
• History of alcohol abuse (defined as \>14 drinks/week) or binge drinking of ≥ 6 drinks at one time).
• Known Cushing's disease.
• Known or suspected adrenal or ovarian androgen secreting tumors.
• Allergy or contraindication to the treatment medications: AI, gonadotropins, CC or hCG.

Sponsors & Collaborators

• Yale University: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• Penn State University: collaborator
• University of Colorado, Denver: collaborator
• University of Michigan: collaborator
• University of Pennsylvania: collaborator
• University of Texas: collaborator
• University of Vermont: collaborator
• Wayne State University: collaborator

Study Sites (14)

University of Alabama Birmingham

Birmingham, Alabama, 35249-7333, United States

Location

University of California, San Francisco

San Francisco, California, 94115, United States

Location

Stanford University Medical Center

Stanford, California, 94305-5317, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Yale University

New Haven, Connecticut, 06511, United States

Location

University of Michigan

Ann Arbor, Michigan, 48108, United States

Location

Wayne State University

Detroit, Michigan, 48201, United States

Location

University of Medicine and Dentistry of New Jersey

Newark, New Jersey, 07601, United States

Location

Carolinas Medical Center

Charlotte, North Carolina, 28232-2861, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Pennsylvania State University College of Medicine

Hershey, Pennsylvania, 17033, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78207, United States

Location

University of Vermont

Burlington, Vermont, 05405, United States

Location

Related Publications (22)

• Kuokkanen S, Seungdamrong A, Santoro N, Lieman H, Sun F, Wild R, Zhang H, Pal L. A relook at the relevance of thyroid stimulating hormone and thyroid autoimmunity for pregnancy outcomes: Analyses of randomized control trials data from Pregnancy in Polycystic Ovary Syndrome and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation. Fertil Steril. 2025 May;123(5):873-882. doi: 10.1016/j.fertnstert.2024.12.005. Epub 2024 Dec 12.

  PMID: 39672366 DERIVED

• Hosseinzadeh P, Peck JD, Burks HR, Souter I, Xing A, Craig LB, Diamond MP, Hansen KR. Follicular phase length is not related to live birth outcome in women with unexplained infertility undergoing ovarian stimulation with intrauterine insemination cycles in a multicenter trial. F S Rep. 2023 Aug 8;4(4):361-366. doi: 10.1016/j.xfre.2023.08.003. eCollection 2023 Dec.

  PMID: 38204957 DERIVED

• 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.

  PMID: 35386508 DERIVED

• 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.

  PMID: 35125179 DERIVED

• 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.

  PMID: 34180998 DERIVED

• 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.

  PMID: 33190149 DERIVED

• 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.

  PMID: 32972733 DERIVED

• 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.

  PMID: 32883514 DERIVED

• 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.

  PMID: 32192596 DERIVED

• 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.

  PMID: 30982604 DERIVED

• 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.

  PMID: 30085177 DERIVED

• 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.

  PMID: 30085176 DERIVED

• 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.

  PMID: 29778387 DERIVED

• 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.

  PMID: 29767754 DERIVED

• 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.

  PMID: 29102040 DERIVED

• 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.

  PMID: 28089575 DERIVED

• 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.

  PMID: 27402910 DERIVED

• 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.

  PMID: 26949110 DERIVED

• 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.

  PMID: 26413816 DERIVED

• 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.

  PMID: 26398071 DERIVED

• 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.

  PMID: 26354094 DERIVED

• 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.

  PMID: 25707331 DERIVED

Related Links

• Reproductive Medicine Network Homepage

MeSH Terms

Conditions

Infertility

Interventions

Letrozole; Aromatase Inhibitors; Clomiphene; Follicle Stimulating Hormone; Gonadotropins

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Gonadotropins, Pituitary; Peptide Hormones; Hormones; Pituitary Hormones, Anterior; Pituitary Hormones; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Heping Zhang, PhD
• Organization: Yale University

heping.zhang@yale.edu

203-785-5185

Study Officials

• Esther Eisenberg, MD, MPH

  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

  STUDY DIRECTOR

• Nanette Santoro, MD

  Albert Einstein College of Medicine

  STUDY CHAIR

• Michael Diamond, MD

  Wayne State University

  PRINCIPAL INVESTIGATOR

• 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 DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 7, 2010
• First Posted: January 8, 2010
• Study Start: June 1, 2010
• Primary Completion: October 1, 2013
• Study Completion: March 1, 2014
• Last Updated: February 2, 2015
• Results First Posted: February 2, 2015

Record last verified: 2015-01

Locations

US (14)