PregnancyPhase 3PPCOSIINCT00719186
Pregnancy in Polycystic Ovary Syndrome II
A Phase 3 study testing Clomiphene citrate and Letrozole in people with Pregnancy and Polycystic Ovary Syndrome, run by Yale University at 12 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, women only
- Conditions the study is for
- Pregnancy, Polycystic Ovary Syndrome
- What is being tested?
- Clomiphene citrate and Letrozole
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 750 participants
- Where
- 12 sitesUnited States
- Study dates
- Feb 2009to May 2013
- 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
- Key Inclusion Criteria (Must have ovulatory dysfunction and either hyperandrogenism or PCO)
- 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.
Who cannot join
- We will exclude subjects with medical conditions that represent contraindications to CC, aromatase inhibitors and/or pregnancy or who are unable to comply with the study procedures. We will exclude subjects with poorly controlled Type I or Type II diabetes; undiagnosed liver disease or dysfunction (based on serum liver enzyme testing); renal disease or abnormal serum renal function; significant anemia; history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident; uncontrolled hypertension, known symptomatic heart disease; history of or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma; undiagnosed vaginal bleeding, and use of other medications known to affect reproductive function or metabolism (e.g., OCP, GnRH agonists and antagonists, antiandrogens, gonadotropins, anti-obesity drugs, somatostatin, diazoxide, ACE inhibitors, and calcium channel blockers). As in PPCOS we will allow a 2 months washout period for subjects who desire to participate and discontinue exclusionary medications (most commonly OCP, but also possibly metformin), and a period of observation or treatment for correctable conditions.
- Couple Inclusion Criteria
- 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.
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- Specific Exclusion Criteria
- 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 known 21-hydroxylase deficiency or other enzyme deficiency leading to the phenotype of congenital adrenal hyperplasia. 21-hydroxylase deficiency will be excluded in all patients by a fasting 17-hydroxyprogesterone (17-OHP) level <2 ng/mL (Azziz, Hincapie et al. 1999 Nov). If relevant, this level should be determined in the follicular phase, because the 17-hydroxyprogesterone level is likely to be elevated beyond this range if the patient is in the luteal phase of an infrequent ovulatory cycle. In the case of elevated fasting 17-OHP levels in the follicular phase, an ACTH stimulation test will be performed. A 1-hour stimulated value > 10 ng/mL will be an exclusion (Moran, Knochenhauer et al. 1998). As 21-hydroxylase deficiency is a congenital condition, any normal level in the past of 17-hydroxyprogesterone allows entry into this study.
- 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.
- Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma. A normal Pap smear result within ACOG guidelines for Pap smear frequency will be required for women 21 and over.
- Patients with a current history of alcohol abuse. Alcohol abuse is defined as > 14 drinks/week or binge drinking.
- Patients enrolled simultaneously into other investigative studies that require medications, proscribe the study medications, limit intercourse, or otherwise prevent compliance with the protocol. Patients who anticipate taking longer than a one month break during the protocol should not be enrolled.
- Patients taking other medications known to affect reproductive function or metabolism. These medications include oral contraceptives, GnRH agonists and antagonists, antiandrogens, gonadotropins, anti-obesity drugs, anti-diabetic drugs such as metformin and thiazolidinediones, somatostatin, diazoxide, ACE inhibitors, and calcium channel blockers. The washout period on all these medications will be two months and a list is found in the appendix.
- Patients with a suspected adrenal or ovarian tumor secreting androgens.
- Patients with suspected Cushing's syndrome.
- Couples with previous sterilization procedures (vasectomy, tubal ligation) which have been reversed. The prior procedure may affect study outcomes, and patients with both a reversed sterilization procedure and PCOS are rare enough that exclusion should not adversely affect recruitment.
- 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.
- 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.
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
United States12 sites
University of Michigan
Ann Arbor, Michigan, 48109
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 Pennsylvania
Philadelphia, Pennsylvania, 19104
Virginia Commonwealth University, School of Medicine
Richmond, Virginia, 23235
University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78229
Stanford University Medical Center
Stanford, California, 94305-5317
About this study
Official title: A 20 Week Double-Blind Randomized Trial of Clomiphene Citrate and Letrozole for the Treatment of Infertility in Women With Polycystic Ovary Syndrome
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:
- 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.
- 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.
- 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.
- The shortest time to pregnancy will be with letrozole.
- 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.
- Improvement in SHBG, testosterone, AMH, and LH levels will be significant predictors of ovulation and conception regardless of treatment.
- DNA polymorphisms in estrogen action genes will predict response to study drug.
- Quality of Life will be better on letrozole than clomiphene.
- Letrozole will be more cost effective at achieving singleton pregnancies than clomiphene.
Read the detailed description
Preliminary data are promising for the use of letrozole to induce ovulation in infertile women with PCOS. However the true magnitude of the effect of letrozole is difficult to discern from prior studies. Therefore we intend to determine the safety and efficacy of letrozole, an aromatase inhibitor, compared to clomiphene citrate, a selective estrogen receptor modulator, in achieving live birth in infertile women with PCOS.
Treatment- After progestin withdrawal, 750 women will be equally randomized to two different treatment arms: A) clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), or B) letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks. Dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of clomiphene a day (x 5 days) or 7.5 mg of letrozole a day (x 5 days).
Statistical Analysis- The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms.
Anticipated time to completion- A total of 4 years will be required to complete the study after start up; 31 month enrollment period, 5 month treatment period, with 9 month additional observation to determine pregnancy outcomes. This will be accomplished by enrolling ~3.45 women with PCOS per center per month over the enrollment period (N = 7 RMN sites).
- Conditions
- Pregnancy, Polycystic Ovary Syndrome
- Being tested
- Clomiphene citrate, Letrozole
- Keywords
- Polycystic Ovary Syndrome, Infertility, Pregnancy, Women
- Medical subject headings
- Polycystic Ovary Syndrome, Infertility
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Clomiphene citrateDrug
Also called Clomid, Serophene
Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
LetrozoleDrug
Also called Femara
Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: Drug: Letrozole |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: as few as 5 months, up to 16 months
Secondary outcomes (4)
Number of Pregnancy
Measured: as few as 5 months, up to 16 months
Number of Ovulations
Measured: as few as 5 months, up to 16 months
Number of Serious Adverse Events
Measured: as few as 5 months, up to 16 months
Neonatal Complication Rate
Measured: September 2008 - December 2011
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jul 2008 (estimated)
- Study startFeb 2009
- Primary completionMay 2013
- Study completionMay 2013
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 (18)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
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 750 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, The University of Texas Health Science Center at San Antonio, 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 MedicineRichard Legro, MD, Principal investigator, Pennsylvania State University College of MedicineRobert Brzyski, MD, PhD, Study director, The University of Texas Health Science Center at San AntonioPeter Casson, MD, Study director, University of VermontMichael Diamond, MD, Study director, Wayne State UniversityHeping Zhang, PhD, Study director, Yale UniversityGregory M Christman, MD, Study director, University of Michigan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00719186
- Sponsor's protocol ID
- RMN-PPCOSII
- Acronym
- PPCOSII
- Status last verified
- May 2018
- First submitted
- 17 Jul 2008
- Last updated
- 14 Jun 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Yun BH, Seo SK, Maher JY, Dowlut-McElroy T, Gomez-Lobo V. Prepregnancy Insulin Resistance and Fertility and Pregnancy Outcomes in Women With Polycystic Ovarian Syndrome. Obstet Gynecol. 2026 May 22. doi: 10.1097/AOG.0000000000006318. Online ahead of print.
PubMed 42166772Kuokkanen 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 39672366Souter 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 33190149Butts 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 30085176Greenwood 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.
PubMed 29969586Evans-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 29778387Seungdamrong 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 29102040Santoro 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.
PubMed 27402910Legro 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.
PubMed 27172435Steiner 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.
PubMed 26413816Kuang 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.
PubMed 26354094Kuang 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.
PubMed 26202922Legro 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.
PubMed 25324541
Study at a glance
From the registry record, last updated by the sponsor on 14 Jun 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A 20 Week Double-Blind Randomized Trial of Clomiphene Citrate and Letrozole for the Treatment of Infertility in Women With Polycystic Ovary Syndrome
- ClinicalTrials.gov ID
- NCT00719186
- Acronym / sponsor ID
- PPCOSII / RMN-PPCOSII
- Conditions
- Pregnancy, Polycystic Ovary Syndrome
- Keywords
- Polycystic Ovary Syndrome, Infertility, Pregnancy, Women
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 750 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, The University of Texas Health Science Center at San Antonio, University of Vermont, Wayne State University
- Study start
- Feb 2009
- Primary completion
- May 2013 (actual)
- Study completion
- May 2013 (actual)
- First posted
- 21 Jul 2008 (estimated)
- Results
- Posted 9 Jun 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
- 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.
- 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.
- The shortest time to pregnancy will be with letrozole.
- 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.
- Improvement in SHBG, testosterone, AMH, and LH levels will be significant predictors of ovulation and conception regardless of treatment.
- DNA polymorphisms in estrogen action genes will predict response to study drug.
- Quality of Life will be better on letrozole than clomiphene.
- Letrozole will be more cost effective at achieving singleton pregnancies than clomiphene.
Detailed description
Preliminary data are promising for the use of letrozole to induce ovulation in infertile women with PCOS. However the true magnitude of the effect of letrozole is difficult to discern from prior studies. Therefore we intend to determine the safety and efficacy of letrozole, an aromatase inhibitor, compared to clomiphene citrate, a selective estrogen receptor modulator, in achieving live birth in infertile women with PCOS.
Treatment- After progestin withdrawal, 750 women will be equally randomized to two different treatment arms: A) clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), or B) letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks. Dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of clomiphene a day (x 5 days) or 7.5 mg of letrozole a day (x 5 days).
Statistical Analysis- The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms.
Anticipated time to completion- A total of 4 years will be required to complete the study after start up; 31 month enrollment period, 5 month treatment period, with 9 month additional observation to determine pregnancy outcomes. This will be accomplished by enrolling ~3.45 women with PCOS per center per month over the enrollment period (N = 7 RMN sites).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A | Active comparator | Drug: Clomiphene citrateClomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks |
| B | Active comparator | Drug: LetrozoleLetrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Key Inclusion Criteria (Must have ovulatory dysfunction and either hyperandrogenism or PCO)
- 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:
Key exclusion criteria (28 listed)
- We will exclude subjects with medical conditions that represent contraindications to CC, aromatase inhibitors and/or pregnancy or who are unable to comply with the study procedures. We will exclude subjects with poorly controlled Type I or Type II diabetes; undiagnosed liver disease or dysfunction (based on serum liver enzyme testing); renal disease or abnormal serum renal function; significant anemia; history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident; uncontrolled hypertension, known symptomatic heart disease; history of or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma; undiagnosed vaginal bleeding, and use of other medications known to affect reproductive function or metabolism (e.g., OCP, GnRH agonists and antagonists, antiandrogens, gonadotropins, anti-obesity drugs, somatostatin, diazoxide, ACE inhibitors, and calcium channel blockers). As in PPCOS we will allow a 2 months washout period for subjects who desire to participate and discontinue exclusionary medications (most commonly OCP, but also possibly metformin), and a period of observation or treatment for correctable conditions.
- Couple Inclusion Criteria
- 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.
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 |
|---|---|---|
| Clomiphene citrateAlso: Clomid, SeropheneClomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks | Drug | A |
| LetrozoleAlso: FemaraLetrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks | Drug | B |
Primary outcome
Live Birth
Time frame: as few as 5 months, up to 16 months
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.
4 secondary outcomes
Number of Pregnancy
Time frame: as few as 5 months, up to 16 months
Number of Ovulations
Time frame: as few as 5 months, up to 16 months
Number of Serious Adverse Events
Time frame: as few as 5 months, up to 16 months
Neonatal Complication Rate
Time frame: September 2008 - December 2011
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jun 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42166772Yun BH, Seo SK, Maher JY, Dowlut-McElroy T, Gomez-Lobo V. Prepregnancy Insulin Resistance and Fertility and Pregnancy Outcomes in Women With Polycystic Ovarian Syndrome. Obstet Gynecol. 2026 May 22. doi: 10.1097/AOG.0000000000006318. Online ahead of print.
- 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 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 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.
- Derived from this study: PubMed 29969586Greenwood 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.
- Derived from this study: PubMed 29778387Evans-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.
- Derived from this study: PubMed 29102040Seungdamrong 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.
- Derived from this study: PubMed 27402910Santoro 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.
- Derived from this study: PubMed 27172435Legro 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.
- Derived from this study: PubMed 26413816Steiner 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.
- Related InfoLink 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
Richard Legro, MD principal investigator
Pennsylvania State University College of Medicine
12 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 Clomiphene citrate and Letrozole in people with Pregnancy and Polycystic Ovary Syndrome, run by Yale University at 12 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 6 inclusion and 28 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 14 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 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 9 Jun 2014). 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?
Live Birth (time frame: as few as 5 months, up to 16 months). 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 NCT00719186, which also lists 18 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 14 Jun 2018.