| City: |
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Hershey |
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State:
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PA |
| Zip Code: |
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17033 |
| Conditions: |
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Pregnancy - Polycystic Ovary Syndrome |
| Purpose: |
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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.
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| Study summary: |
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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). |
| Criteria: |
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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. |
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| Study is available at: |
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Pennsylvania State University College of Medicine
Hershey, PA 17033
United States
Primary Contact:
Richard Legro, MD
Email: RSL1@PSU.EDU
Phone: 717-531-8478
Secondary Contact:
Heping Zhang, PHD
Email: rmn-Coordinators@panlists.yale.edu
Phone: (203) 785-5185 |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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March 22, 2011 |
Modifications to
this listing: |
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above to view all information about this clinical trial. |
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