Pregnancy in Polycystic Ovary Syndrome II (PPCOSII)

May 15, 2018 updated by: Heping Zhang, Yale University

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:

  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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

750

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35249-7333
        • University of Alabama Birmingham
    • California
      • Stanford, California, United States, 94305-5317
        • Stanford University Medical Center
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado
    • Connecticut
      • New Haven, Connecticut, United States, 06511
        • Yale University
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan
      • Detroit, Michigan, United States, 48201
        • Wayne State University
    • North Carolina
      • Charlotte, North Carolina, United States, 28232-2861
        • Carolinas Medical Center
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 17033
        • Pennsylvania State University College of Medicine
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania
    • Texas
      • San Antonio, Texas, United States, 78229
        • University of Texas Health Science Center at San Antonio
    • Vermont
      • Burlington, Vermont, United States, 05405
        • University of Vermont
    • Virginia
      • Richmond, Virginia, United States, 23235
        • Virginia Commonwealth University, School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 36 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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/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.

  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 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.
    3. 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.

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 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

  1. Sperm concentration of 14 million/mL in at least one ejaculate within the last year, with at least some motile sperm.
  2. Ability to have regular intercourse during the ovulation induction phase of the study.
  3. 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.
  4. No previous sterilization procedures (vasectomy, tubal ligation) that have been reversed. The prior procedure may affect study outcomes.

Specific Exclusion Criteria

  1. Current pregnancy.
  2. 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.
  3. 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.
  4. 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.
  5. Patients with menopausal levels of FSH (> 15 mIU/mL). A normal level within the last year is adequate for entry.
  6. 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.
  7. 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.
  8. Patients with liver disease defined as AST or ALT > 2 times normal or total bilirubin >2.5 mg/dL.
  9. Patients with renal disease defined as BUN > 30 mg/dL or serum creatinine> 1.4 mg/dL.
  10. Patients with significant anemia (Hemoglobin < 10 g/dL).
  11. Patients with a history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident.
  12. Patients with known heart disease that is likely to be exacerbated by pregnancy.
  13. 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.
  14. Patients with a current history of alcohol abuse. Alcohol abuse is defined as > 14 drinks/week or binge drinking.
  15. 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.
  16. 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.
  17. Patients with a suspected adrenal or ovarian tumor secreting androgens.
  18. Patients with suspected Cushing's syndrome.
  19. 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.
  20. 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.
  21. 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: A
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
Other Names:
  • Clomid
  • Serophene
Active Comparator: B
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
Other Names:
  • Femara

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
as few as 5 months, up to 16 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Number of Pregnancy
Time Frame: as few as 5 months, up to 16 months
as few as 5 months, up to 16 months
Number of Ovulations
Time Frame: as few as 5 months, up to 16 months
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
as few as 5 months, up to 16 months
Neonatal Complication Rate
Time Frame: September 2008 - December 2011
September 2008 - December 2011

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

University of Colorado, Denver
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Pennsylvania
Wayne State University
University of Michigan
University of Vermont
Penn State University
The University of Texas Health Science Center at San Antonio

Investigators

  • Principal Investigator: Richard Legro, MD, Pennsylvania State University College of Medicine
  • Study Director: Michael Diamond, MD, Wayne State University
  • Study Director: Gregory M Christman, MD, University of Michigan
  • Study Director: William D Schlaff, MD, University of Colorado Denver Health Science Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2009

Primary Completion (Actual)

May 1, 2013

Study Completion (Actual)

May 1, 2013

Study Registration Dates

First Submitted

July 17, 2008

First Submitted That Met QC Criteria

July 18, 2008

First Posted (Estimate)

July 21, 2008

Study Record Updates

Last Update Posted (Actual)

June 14, 2018

Last Update Submitted That Met QC Criteria

May 15, 2018

Last Verified

May 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RMN-PPCOSII

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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