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Pregnancy in Polycystic Ovary Syndrome II (PPCOSII)
This study is not yet open for participant recruitment.
Verified by Yale University, September 2008
Sponsors and Collaborators: Yale University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Penn State University
University of Colorado at Denver and Health Sciences Center
University of Michigan
University of Pennsylvania
University of Texas
University of Vermont
Wayne State University
Information provided by: Yale University
ClinicalTrials.gov Identifier: NCT00719186
  Purpose

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. 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. 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. 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. The shortest time to pregnancy will be with letrozole.
  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. Improvement in SHBG, testosterone, AMH, and LH levels will be significant predictors of ovulation and conception regardless of treatment.
  7. DNA polymorphisms in estrogen action genes will predict response to study drug.
  8. Quality of Life will be better on letrozole than clomiphene.
  9. Letrozole will be more cost effective at achieving singleton pregnancies than clomiphene.

Condition Intervention Phase
Pregnancy
Polycystic Ovary Syndrome
Drug: Clomiphene citrate
Drug: Letrozole
Phase III

MedlinePlus related topics: Infertility
Drug Information available for: Citric acid Sodium Citrate Clomiphene citrate Clomiphene Enclomiphene Zuclomiphene Letrozole
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Efficacy 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

Further study details as provided by Yale University:

Primary Outcome Measures:
  • 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. [ Time Frame: September 2008 to September 2012 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Singleton live birth rate [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: No ]
  • Abortion rate [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: Yes ]
  • Time to pregnancy [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: No ]
  • Ovulation rate [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: No ]
  • Pregnancy complication rate [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: Yes ]
  • Birth weight [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: No ]
  • Neonatal complication rate [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: Yes ]
  • DNA polymorphisms [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: No ]
  • Quality of life [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: Yes ]
  • Cost effectiveness [ Time Frame: September 2008 - December 2011 ] [ Designated as safety issue: No ]

Estimated Enrollment: 750
Study Start Date: December 2008
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Clomiphene 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
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
Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks

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).

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

The patient population will consist of 750 infertile women with PCOS with ovulatory dysfunction and either one of the remaining two criteria, hyperandrogenism (clinical or biochemical) or polycystic ovaries on ultrasound, with exclusion of secondary causes of PCOS. Additionally, the couple will have no other major infertility factor, and the subject will have at least one patent fallopian tube and a normal uterine cavity, and a partner with a sperm concentration of 14 million/mL in at least one ejaculate.

Inclusion Criteria:

  • Key Inclusion Criteria (Must have ovulatory dysfunction and either hyperandrogenism or PCO)

    1. 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/dL 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/dL will be evidence of ovulatory dysfunction and qualify as anovulation.
    2. Hyperandrogenism (either Hirsutism or Hyperandrogenemia) or Polycystic Ovaries on Ultrasound:

      1. 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.
      2. Hyperandrogenemia will be defined as an elevated total testosterone, or free androgen index (FAI). Outside lab values obtained within the last year documenting elevated T or FAI levels are sufficient to meet criteria of hyperandrogenemia.
      3. Polycystic Ovaries on Ultrasound: 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.

Exclusion Criteria:

  • 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 1 or 2 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, anti-androgens, gonadotropins, anti-obesity drugs, somatostatin, diazoxide, ACE inhibitors, and calcium channel blockers). As in PPCOS we will allow a 3 mos 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00719186

Contacts
Contact: Heping Zhang, PHD (203) 785-5185 rmn-Coordinators@masal.med.yale.edu
Contact: Meizhuo Zhang, PHD (203) 785-6759 meizhuo.zhang@yale.edu

Locations
United States, Colorado
University of Colorado
Aurora,, Colorado, United States, 80045
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06511
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Wayne State University
Detroit, Michigan, United States, 48201
United States, Pennsylvania
Pennsylvania State University College of Medicine
Hershey, Pennsylvania, United States, 17033
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States, 78229
United States, Vermont
University of Vermont
Burlington, Vermont, United States, 05405
Sponsors and Collaborators
Yale University
Penn State University
University of Colorado at Denver and Health Sciences Center
University of Michigan
University of Pennsylvania
University of Texas
University of Vermont
Wayne State University
Investigators
Study Director: Esther Eisenberg, MD, MPH Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study Chair: Nanette Santoro, MD Albert Einstein College of Medicine of Yeshiva University
Principal Investigator: Richard Legro, MD Pennsylvania State University College of Medicine
Study Director: Robert Brzyski, MD, PhD University of Texas
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
  More Information

Related Info  This link exits the ClinicalTrials.gov site

Responsible Party: Penn State University Hershey Medical Center ( Richard Legro, MD, Professor )
Study ID Numbers: RMN-PPCOSII
Study First Received: July 17, 2008
Last Updated: September 22, 2008
ClinicalTrials.gov Identifier: NCT00719186  
Health Authority: United States: Food and Drug Administration;   United States: Federal Government

Keywords provided by Yale University:
Polycystic Ovary Syndrome
Infertility
Pregnancy
Women

Study placed in the following topic categories:
Genital Diseases, Female
Infertility
Gonadal Disorders
Citric Acid
Polycystic Ovary Syndrome
Clomiphene
Endocrine System Diseases
Letrozole
Endocrinopathy
Ovarian Diseases
Cysts
Ovarian Cysts

Additional relevant MeSH terms:
Estrogen Antagonists
Disease
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Hormone Antagonists
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Enzyme Inhibitors
Reproductive Control Agents
Selective Estrogen Receptor Modulators
Pharmacologic Actions
Adnexal Diseases
Estrogen Receptor Modulators
Neoplasms
Pathologic Processes
Therapeutic Uses
Syndrome
Fertility Agents, Female
Fertility Agents
Aromatase Inhibitors

ClinicalTrials.gov processed this record on January 13, 2009