Pregnancy in Polycystic Ovary Syndrome II
Condition: Pregnancy; Polycystic Ovary Syndrome
MeSH terms: Polycystic Ovary Syndrome; Syndrome
Study type: Interventional
Phase: Phase 3

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. 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.
    

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).
    

Intervention name(s): Clomiphene citrate; Letrozole
Intervention type(s): Drug; Drug
Intervention description(s): Clomiphene citrate 50 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks; Letrozole 2.5 mg every day for 5 days (day 3-7 of cycle), for a total of 5 cycles or 20 weeks
Other intervention name(s): Clomid; Serophene; Femara
Intervention MeSH terms: Letrozole; Clomiphene; Enclomiphene; Zuclomiphene
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Polycystic Ovary Syndrome; Infertility; Pregnancy; Women