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:

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 Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Efficacy Study

Study Primary Completion Date: February 2013

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).

Intervention(s) in this Clinical Trial

• 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
• 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

Arms, Groups and Cohorts in this Clinical Trial

• 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
• 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

Primary 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
    Safety Issue?: Yes

Secondary Measures

• Singleton live birth rate
  • Time Frame: September 2008 - December 2011
    Safety Issue?: No
• Abortion rate
  • Time Frame: September 2008 - December 2011
    Safety Issue?: Yes
• Time to pregnancy
  • Time Frame: September 2008 - December 2011
    Safety Issue?: No
• Ovulation rate
  • Time Frame: September 2008 - December 2011
    Safety Issue?: No
• Pregnancy complication rate
  • Time Frame: September 2008 - December 2011
    Safety Issue?: Yes
• Birth weight
  • Time Frame: September 2008 - December 2011
    Safety Issue?: No
• Neonatal complication rate
  • Time Frame: September 2008 - December 2011
    Safety Issue?: Yes
• DNA polymorphisms
  • Time Frame: September 2008 - December 2011
    Safety Issue?: No
• Quality of life
  • Time Frame: September 2008 - December 2011
    Safety Issue?: Yes
• Cost effectiveness
  • Time Frame: September 2008 - December 2011
    Safety Issue?: No

• 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.

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 40 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Yale University

Overall Clinical Trial Officials and Contacts

Esther Eisenberg, MD, MPH Study Director Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)  

Overall Contact: Heping Zhang, PHD (203) 785-5185 rmn-Coordinators@panlists.yale.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00719186

Study ID Number: RMN-PPCOSII

ClinicalTrials.gov Identifier: NCT00719186

Health Authority: United States: Food and Drug Administration