PregnancyPhase 3AMIGOSNCT01044862
Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation
A Phase 3 study testing Letrozole (aromatase inhibitor), Clomiphene Citrate and Follicle Stimulating Hormone (gonadotropin) in people with Pregnancy and Unexplained Infertility, run by Yale University at 14 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, women only
- Conditions the study is for
- Pregnancy, Unexplained Infertility
- What is being tested?
- Letrozole (aromatase inhibitor), Clomiphene Citrate and Follicle Stimulating Hormone (gonadotropin)
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 900 participants
- Where
- 14 sitesUnited States
- Study dates
- Jun 2010to Mar 2014
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
- 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.
Show all 24Show fewer
- 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.
- Couples with previous sterilization procedures (e.g. vasectomy, tubal ligation) which have been reversed.
- 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.
- 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.
- Known moderate or severe endometriosis
- Known polycystic ovarian syndrome as evidenced by anovulation or oligoovulation, hirsutism and/or elevated testosterone levels, and ovarian morphology on ultrasound examination.
- Donated semen.
- Couples in which either partner is legally married to someone else.
- Medical conditions that are contraindications to pregnancy.
Trial locations and contacts
14 sites in 1 country.
14 sites in 1 country
United States14 sites
University of Michigan
Ann Arbor, Michigan, 48108
University of Colorado
Aurora, Colorado, 80045
University of Alabama Birmingham
Birmingham, Alabama, 35249-7333
University of Vermont
Burlington, Vermont, 05405
Carolinas Medical Center
Charlotte, North Carolina, 28232-2861
Wayne State University
Detroit, Michigan, 48201
Pennsylvania State University College of Medicine
Hershey, Pennsylvania, 17033
Yale University
New Haven, Connecticut, 06511
University of Medicine and Dentistry of New Jersey
Newark, New Jersey, 07601
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78207
University of California, San Francisco
San Francisco, California, 94115
Stanford University Medical Center
Stanford, California, 94305-5317
About this study
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.
Read the 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.
- Conditions
- Pregnancy, Unexplained Infertility
- Being tested
- Letrozole (aromatase inhibitor), Clomiphene Citrate, Follicle Stimulating Hormone (gonadotropin)
- Keywords
- Pregnancy, Infertility, Ovarian stimulation, Aromatase inhibitors, Follicle Stimulating Hormone
- Medical subject headings
- Infertility
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
Clomiphene CitrateDrug
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.
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Follicle Stimulating Hormone (gonadotropin) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Multiple Gestation Rate Following Recruitment of Multiple Follicular Development With an AI, as Compared to CC and FSH.
Measured: 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
Measured: Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks
Time to Pregnancy
Measured: Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks
Live Birth Rate
Measured: Participants were followed for the duration of their treatment and, if pregnant through 6 weeks post-delivery, up to 66 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jan 2010 (estimated)
- Study startJun 2010
- Primary completionOct 2013
- Study completionMar 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (22)Papers the sponsor has linked to this study.
- Other trials for PregnancyStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 900 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- 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
- Responsible party
- Principal investigator, Heping Zhang, Yale University
- Investigators
- Esther Eisenberg, MD, MPH, Study director, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)Nanette Santoro, MD, Study chair, Albert Einstein College of MedicineMichael Diamond, MD, Principal investigator, Wayne State UniversityRichard Legro, MD, Study director, Pennsylvania State University College of MedicineWilliam Schlaff, MD, Study director, University of Colorado Denver Health Science CenterGregory Christman, MD, Study director, University of MichiganChristos Coutifaris, MD, Study director, University of PennsylvaniaRobert Brzyski, MD, PhD, Study director, The University of Texas Health Science Center at San Antonio
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01044862
- Sponsor's protocol ID
- RMN-AMIGOS
- Other IDs
- 3U10HD055925-02S1, 5U10HD055925, 3U10HD039005-08S1, 5U10HD039005
- Acronym
- AMIGOS
- Status last verified
- Jan 2015
- First submitted
- 7 Jan 2010
- Last updated
- 2 Feb 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 39672366Hosseinzadeh 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.
PubMed 38204957Gavrizi 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.
PubMed 35386508Souter 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.
PubMed 35125179Eisenberg 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.
PubMed 34180998Engmann 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.
PubMed 33190149Quaas 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.
PubMed 32972733Kaing 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.
PubMed 32883514Wang 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.
PubMed 32192596Trussell 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.
PubMed 30982604Barrett 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.
PubMed 30085177Butts 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.
PubMed 30085176Evans-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.
PubMed 29778387Hansen 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.
PubMed 29767754Seungdamrong 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.
PubMed 29102040
Study at a glance
From the registry record, last updated by the sponsor on 2 Feb 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation
- ClinicalTrials.gov ID
- NCT01044862
- Acronym / sponsor ID
- AMIGOS / RMN-AMIGOS
- Conditions
- Pregnancy, Unexplained Infertility
- Keywords
- Pregnancy, Infertility, Ovarian stimulation, Aromatase inhibitors, Follicle Stimulating Hormone
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 900 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- 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
- Study start
- Jun 2010
- Primary completion
- Oct 2013 (actual)
- Study completion
- Mar 2014 (actual)
- First posted
- 8 Jan 2010 (estimated)
- Results
- Posted 2 Feb 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Aromatase Inhibitors (AI) | Active comparator | 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. |
| Clomiphene Citrate (CC) | Active comparator | Drug: Clomiphene CitrateCC 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. |
| Follicle Stimulating Hormone (FSH) | Active comparator | 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. |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (24 listed)
- 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.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Drug | Aromatase Inhibitors (AI) |
| Clomiphene CitrateCC 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) |
| 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. | Drug | Follicle Stimulating Hormone (FSH) |
Primary outcome
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
3 secondary outcomes
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
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
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Feb 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 39672366Kuokkanen 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.
- Derived from this study: PubMed 38204957Hosseinzadeh 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.
- Derived from this study: PubMed 35386508Gavrizi 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.
- Derived from this study: PubMed 35125179Souter 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.
- Derived from this study: PubMed 34180998Eisenberg 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.
- Derived from this study: PubMed 33190149Engmann 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.
- Derived from this study: PubMed 32972733Quaas 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.
- Derived from this study: PubMed 32883514Kaing 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.
- Derived from this study: PubMed 32192596Wang 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.
- Derived from this study: PubMed 30982604Trussell 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.
- Derived from this study: PubMed 30085177Barrett 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.
- Derived from this study: PubMed 30085176Butts 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.
- Reproductive Medicine Network HomepageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Esther Eisenberg, MD, MPH study director
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Nanette Santoro, MD study chair
Albert Einstein College of Medicine
Michael Diamond, MD principal investigator
Wayne State University
14 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Letrozole (aromatase inhibitor), Clomiphene Citrate and Follicle Stimulating Hormone (gonadotropin) in people with Pregnancy and Unexplained Infertility, run by Yale University at 14 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Feb 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Feb 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01044862, which also lists 22 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2015.