Pregnancy in Polycystic Ovary Syndrome II

NCT00719186 | Completed Phase 3 Results DMC

• 1 other identifier: RMN-PPCOSII
• Study Type: interventional
• Target: 750
• Locations: 1 country
• Sites: 12

Brief Summary

The primary research hypothesis is that ovulation induction with an aromatase inhibitor (letrozole) is more likely to result in live birth than ovulation induction with a selective estrogen receptor modulator (clomiphene citrate) in infertile women with PCOS. A safety hypothesis will also be incorporated into the primary research hypothesis in which we hypothesize both treatments are equally safe for mother and child. Secondary research hypotheses include:

1. 1.Treatment with letrozole is more likely to result in singleton pregnancy compared to treatment with clomiphene citrate. Singleton pregnancy is defined as presence of a single intrauterine gestational sac with a single fetal pole and observable heart motion.
2. 2.Treatment with letrozole will less likely result in a first trimester intrauterine fetal demise than treatment with clomiphene citrate. A first trimester IUFD is defined as a pregnancy that ends before 13 weeks gestation.
3. 3.Treatment with letrozole is more likely to result in ovulation (increased ovulation rate) compared to treatment with clomiphene citrate. Ovulation is defined as a midluteal progesterone level ≥ 3 ng/mL.
4. 4.The shortest time to pregnancy will be with letrozole.
5. 5.Age, body mass index, SHBG, testosterone, LH, Anti-Mullerian Hormone (AMH), and degree of hirsutism and acne will be significant predictors of ovulation and conception regardless of treatment.
6. 6.Improvement in SHBG, testosterone, AMH, and LH levels will be significant predictors of ovulation and conception regardless of treatment.
7. 7.DNA polymorphisms in estrogen action genes will predict response to study drug.
8. 8.Quality of Life will be better on letrozole than clomiphene.
9. 9.Letrozole will be more cost effective at achieving singleton pregnancies than clomiphene.

Conditions

Pregnancy; Polycystic Ovary Syndrome

Keywords

Polycystic Ovary Syndrome; Infertility; Pregnancy; Women

Outcome Measures

Primary Outcomes (1)

• Live Birth

  The primary outcome measure is the occurrence of a live birth during the study period. Safety measures will be the number and type of reported adverse events in subjects and offspring.

  as few as 5 months, up to 16 months

Secondary Outcomes (4)

• Number of Pregnancy

  as few as 5 months, up to 16 months

• Number of Ovulations

  as few as 5 months, up to 16 months

• Number of Serious Adverse Events

  as few as 5 months, up to 16 months

• Neonatal Complication Rate

  September 2008 - December 2011

Study Arms (2)

A

ACTIVE COMPARATOR

Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks

Drug: Clomiphene citrate

B

ACTIVE COMPARATOR

Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks

Drug: Letrozole

Interventions

Clomiphene citrate DRUG

Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks

Also known as: Clomid, Serophene

A

Letrozole DRUG

Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks

Also known as: Femara

B

Eligibility Criteria

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

You may qualify if:

• Chronic anovulation or oligomenorrhea: defined as spontaneous intermenstrual periods of ≥45 days or a total of ≤8 menses per year, or for women with suspected anovulatory bleeding, a midluteal serum progesterone level \< 3 ng/mL is indicative of chronic anovulation. For women who have been on ovarian suppressive therapy or other confounding medication (i.e. insulin sensitizing agents) within the last year prior to the study, a history of ≤8 menses per year prior to the initiation of this prior therapy will qualify as evidence of oligomenorrhea. For women with more regular bleeding patterns, but who are suspected to be experiencing anovulatory bleeding, a midluteal progesterone level \< 3ng/mL will be evidence of ovulatory dysfunction and qualify as anovulation. Undiagnosed persistent vaginal bleeding should be diagnosed and treated prior to enrollment.
• Hyperandrogenism (either Hirsutism or Hyperandrogenemia) or Polycystic Ovaries on Ultrasound:
• Hirsutism is determined by a modified Ferriman-Gallwey Score \>8 at screening exam (Hatch, Rosenfield et al. 1981 Aug 1). Subjects who have hirsutism do not need local or core labs documenting elevated androgen levels.
• Hyperandrogenemia can be determined from local labs. Local cutoffs will be pre-determined by each site prior to study initiation. Hyperandrogenemia will be defined as an elevated total testosterone, or free androgen index (FAI)(in our lab at Penn State College of Medicine a total T \> 50 ng/dL or a free androgen index \>5) will allow entry into the study (Legro, Driscoll et al. 1998). The FAI is calculated from measurable values for total T and SHBG, as previously described (Miller, Rosner et al. 2004), using the following equation: (FAI = Total testosterone in nmol/L / SHBG in nmol/L) X 100. Outside lab values obtained within the last year documenting elevated T or FAI levels are sufficient to meet criteria of hyperandrogenemia.
• Polycystic Ovaries on Ultrasound: We will use the revised Rotterdam criteria for diagnosing polycystic ovaries (Balen, Laven et al. 2003). PCO will be defined as either an ovary that contains 12 or more follicles measuring 2-9 mm in diameter, or an increased ovarian volume (\> 10 cm3) on one ovary for entry into the study. If there is a follicle \> 10 mm in diameter, the scan should be repeated at a time of ovarian quiescence in order to calculate volume and area if the subject does not otherwise qualify for the study. The presence of a single polycystic ovary (PCO), either by volume or morphology, is sufficient to provide the diagnosis.

You may not qualify if:

• Sperm concentration of 14 million/mL in at least one ejaculate within the last year, with at least some motile sperm.
• Ability to have regular intercourse during the ovulation induction phase of the study.
• At least one patent tube and normal uterine cavity as determined by sonohysterogram, hysterosalpingogram, or hysteroscopy/laparoscopy within the last 3 years. 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.
• No previous sterilization procedures (vasectomy, tubal ligation) that have been reversed. The prior procedure may affect study outcomes.
• Current pregnancy.
• 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 where the implants are still in place. A one-month washout will be required for patients on oral cyclic progestins.
• Patients with hyperprolactinemia (defined as two prolactin levels at least one week apart \> 30 ng/mL or as determined by local normative values). The goal of eliminating patients with documented hyperprolactinemia is to decrease the heterogeneity of the PCOS population. These patients may be candidates for ovulation induction with alternate regimens (dopamine agonists). A normal level within the last year or on treatment is adequate for entry.
• Patients with menopausal levels of FSH (\> 15 mIU/mL). A normal level within the last year is adequate for entry.
• Patients with uncorrected thyroid disease (defined as TSH \< 0.2 mIU/mL or \>5.5 mIU/mL). A normal level within the last year is adequate for entry.
• Patients diagnosed with Type I or Type II diabetes who are poorly controlled (defined as a glycohemoglobin level \> 7.0%), or patients receiving antidiabetic medications such as insulin, thiazolidinediones, acarbose, or sulfonylureas likely to confound the effects of study medication; patients currently receiving metformin XR for a diagnosis of Type I or Type II diabetes or for PCOS are also specifically excluded.
• Patients with liver disease defined as AST or ALT \> 2 times normal or total bilirubin \>2.5 mg/dL.
• Patients with renal disease defined as BUN \> 30 mg/dL or serum creatinine\> 1.4 mg/dL.
• Patients with significant anemia (Hemoglobin \< 10 g/dL).
• Patients with a history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident.
• Patients with known heart disease that is likely to be exacerbated by pregnancy.

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
• The University of Texas Health Science Center at San Antonio: collaborator
• University of Vermont: collaborator
• Wayne State University: collaborator

Study Sites (12)

University of Alabama Birmingham

Birmingham, Alabama, 35249-7333, 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, 48109, United States

Location

Wayne State University

Detroit, Michigan, 48201, United States

Location

Carolinas Medical Center

Charlotte, North Carolina, 28232-2861, 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, 78229, United States

Location

University of Vermont

Burlington, Vermont, 05405, United States

Location

Virginia Commonwealth University, School of Medicine

Richmond, Virginia, 23235, United States

Location

Related Publications (17)

• 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

• 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

• 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

• Greenwood EA, Pasch LA, Cedars MI, Legro RS, Huddleston HG; Eunice Kennedy Shriver National Institute of Child Health and Human Development Reproductive Medicine Network. Association among depression, symptom experience, and quality of life in polycystic ovary syndrome. Am J Obstet Gynecol. 2018 Sep;219(3):279.e1-279.e7. doi: 10.1016/j.ajog.2018.06.017. Epub 2018 Jun 30.

  PMID: 29969586 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

• 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

• 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

• Legro RS, Dodson WC, Kunselman AR, Stetter CM, Kris-Etherton PM, Williams NI, Gnatuk CL, Estes SJ, Allison KC, Sarwer DB, Diamond MP, Schlaff WD, Casson PR, Christman GM, Barnhart KT, Bates GW, Usadi R, Lucidi S, Baker V, Zhang H, Eisenberg E, Coutifaris C, Dokras A. Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS. J Clin Endocrinol Metab. 2016 Jul;101(7):2658-66. doi: 10.1210/jc.2016-1659. Epub 2016 May 12.

  PMID: 27172435 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

• 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

• Kuang H, Jin S, Hansen KR, Diamond MP, Coutifaris C, Casson P, Christman G, Alvero R, Huang H, Bates GW, Usadi R, Lucidi S, Baker V, Santoro N, Eisenberg E, Legro RS, Zhang H; Reproductive Medicine Network. Identification and replication of prediction models for ovulation, pregnancy and live birth in infertile women with polycystic ovary syndrome. Hum Reprod. 2015 Sep;30(9):2222-33. doi: 10.1093/humrep/dev182. Epub 2015 Jul 22.

  PMID: 26202922 DERIVED

• Legro RS, Chen G, Kunselman AR, Schlaff WD, Diamond MP, Coutifaris C, Carson SA, Steinkampf MP, Carr BR, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Myers ER, Zhang H, Foulds J; Reproductive Medicine Network. Smoking in infertile women with polycystic ovary syndrome: baseline validation of self-report and effects on phenotype. Hum Reprod. 2014 Dec;29(12):2680-6. doi: 10.1093/humrep/deu239. Epub 2014 Oct 16.

  PMID: 25324541 DERIVED

• Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, Christman GM, Huang H, Yan Q, Alvero R, Haisenleder DJ, Barnhart KT, Bates GW, Usadi R, Lucidi S, Baker V, Trussell JC, Krawetz SA, Snyder P, Ohl D, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014 Jul 10;371(2):119-29. doi: 10.1056/NEJMoa1313517.

  PMID: 25006718 DERIVED

• Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Alvero R, Casson P, Christman GM, Huang H, Yan Q, Haisenleder DJ, Barnhart KT, Bates GW, Usadi R, Lucidi R, Baker V, Trussell JC, Krawetz SA, Snyder P, Ohl D, Santoro N, Eisenberg E, Zhang H; National Institute of Child Health and Human Development Reproductive Medicine Network. The Pregnancy in Polycystic Ovary Syndrome II study: baseline characteristics and effects of obesity from a multicenter randomized clinical trial. Fertil Steril. 2014 Jan;101(1):258-269.e8. doi: 10.1016/j.fertnstert.2013.08.056. Epub 2013 Oct 21.

  PMID: 24156957 DERIVED

• Schlaff WD, Zhang H, Diamond MP, Coutifaris C, Casson PR, Brzyski RG, Christman GM, Barnhart KT, Trussell JC, Krawetz SA, Snyder PJ, Ohl D, Santoro N, Eisenberg E, Huang H, Legro RS; Reproductive Medicine Network. Increasing burden of institutional review in multicenter clinical trials of infertility: the Reproductive Medicine Network experience with the Pregnancy in Polycystic Ovary Syndrome (PPCOS) I and II studies. Fertil Steril. 2011 Jul;96(1):15-8. doi: 10.1016/j.fertnstert.2011.05.069. Epub 2011 Jun 8.

  PMID: 21645894 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Polycystic Ovary Syndrome; Infertility

Interventions

Clomiphene; Letrozole

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Nitriles; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Heping Zhang
• Organization: Yale University

rmn-dcc@panlists.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

• Richard Legro, MD

  Pennsylvania State University College of Medicine

  PRINCIPAL INVESTIGATOR

• Robert Brzyski, MD, PhD

  The University of Texas Health Science Center at San Antonio

  STUDY DIRECTOR

• Peter Casson, MD

  University of Vermont

  STUDY DIRECTOR

• Michael Diamond, MD

  Wayne State University

  STUDY DIRECTOR

• Heping Zhang, PhD

  Yale University

  STUDY DIRECTOR

• Gregory M Christman, MD

  University of Michigan

  STUDY DIRECTOR

• Christos Coutifaris, MD

  University of Pennsylvania

  STUDY DIRECTOR

• William D Schlaff, MD

  University of Colorado Denver Health Science Center

  STUDY DIRECTOR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: July 17, 2008
• First Posted: July 21, 2008
• Study Start: February 1, 2009
• Primary Completion: May 1, 2013
• Study Completion: May 1, 2013
• Last Updated: June 14, 2018
• Results First Posted: June 9, 2014

Record last verified: 2018-05

Locations

US (12)