Combined Letrozole and Clomid in Women With Infertility and PCOS

Study Overview
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Brief Summary
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This study evaluates the addition of clomid to letrozole for the treatment of infertility in women with polycystic ovary syndrome. Half of the participants will receive letrozole and clomid in combination, while the other half will receive letrozole alone.

Detailed Description
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Letrozole and Clomid are both used for ovulation induction, but they have different mechanisms of action. Letrozole has been shown to be superior to clomid in achieving live birth rates in women with infertility and polycystic ovary syndrome. However, the combination of these medications has not been studied. This is a pilot study to evaluate if the combination treatment has improved efficacy as measured by ovulation rate. This is a randomized controlled trial of letrozole versus letrozole and clomiphene citrate (CC) for one menstrual cycle. Women will be randomized in a 1:1 ratio to receive letrozole 2.5 mg or combination of letrozole 2.5 mg and clomiphene 50 mg for 5 days on days 3-7 of menstrual cycle. The women and their partners will be instructed to have regular intercourse with the intent to conceive during the cycle. Patients will have an transvaginal ultrasound mid cycle and to evaluate number of follicles (>15 mm), follicle size, endometrial thickness and pattern. Patients will have mid- luteal phase progesterone level drawn to evaluate ovulation. Side effect profile will also be monitored.

Official Title
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Combined Letrozole and Clomid in Polycystic Ovary Syndrome: a Randomized Control Trial of Combination of Letrozole and Clomiphene Citrate or Letrozole Alone for the Treatment of Infertility in Women With Polycystic Ovary Syndrome

Conditions
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Polycystic Ovary Syndrome, Infertility

Intervention / Treatment
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* Drug: Clomiphene
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to comply with all study procedures and be available for the duration of the study Diagnosis of infertility: Inability of couple to achieve successful pregnancy after 12 months of regular timed unprotected intercourse in women less than 35 years of age; and after 6 months of regular intercourse without use of contraception in women 35 years and older Diagnosis of polycystic ovary syndrome based on Revised Rotterdam criteria Ability to have regular intercourse during the ovulation induction phase of the study Normal sperm concentration of 15 million/mL and with normal motility of > 40% according to World Health Organization cutoff points, in at least one ejaculate during the previous year Exclusion Criteria: Current pregnancy Current use of hormonal contraception; use of any type of combined contraceptive or oral progestins within the past month; or use of hormonal implants or depo progestins within the past 3 months Other known cause of infertility: endometriosis, tubal factor, uterine abnormalities Uncorrected thyroid disease Untreated hyperprolactinemia. Medical conditions in which avoiding pregnancy is recommended until under improved control: poorly controlled Type 1 or Type 2 diabetes, poorly controlled hypertension Contraindications to clomiphene citrate: hypersensitivity to CC or any of its components, history of liver disease or known liver disease, unknown cause of abnormal uterine bleeding, or intracranial lesion Contraindications to letrozole: hypersensitivity to letrozole or any of its components. Use of medications known to affect reproductive function or metabolism or that are an absolute contraindication during pregnancy within the past month. If patients are suspected based on clinical findings for other etiologies that mimic PCOS, work up must be completed to exclude other etiologies prior to enrollment (i.e. Cushing's syndrome, androgen-secreting tumor).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Letrozole<br>Letrozole 2.5 mg orally for 5 days on cycle days 3-7 | Drug: Letrozole<br> <br> * Other names: femara;|
| Experimental: Letrozole + Clomiphene<br>Letrozole 2.5 mg orally for 5 days on cycle days 3-7 AND Clomid 50 mg orally for 5 days on cycle days 3-7 | Drug: Clomiphene<br> <br> * Other names: clomiphene citrate;Drug: Letrozole<br> <br> * Other names: femara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Ovulation Measured by Mid-luteal Progesterone Level | Ovulation: mid-luteal progesterone > /=3 ng/mL. No ovulation: mid-luteal progesterone <3ng/mL. | 7 days following LH surge or at cycle day 21 if no LH surge was detected | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Developing Follicles | Number of follicles measuring > 10mm on ultrasound | Cycle day 12-14 | 
| Size of Largest Developing Follicle | Size of largest follicle on ultrasound | Cycle day 12-14 | 
| Endometrial Thickness | Thickness of endometrial lining assessed by ultrasound | Cycle day 12-14 | 
| Conception | Conception: a positive serum or urinary test of hCG; No conception: Neither a positive serum or urinary test of hCG | 5 weeks after treatment | 
| Clinical Pregnancy | Clinical Pregnancy: an intrauterine pregnancy with fetal heart motion determined by ultrasonography; No Clinical Pregnancy: no intrauterine pregnancy with fetal heart motion determined by ultrasonography | 6-7 weeks after treatment | 
| Multiple Gestation | Multiple Gestation: an intrauterine pregnancy with multiple fetal heart rates determined by ultrasonography; No Multiple Gestation: either no intrauterine pregnancy, or an intrauterine pregnancy with a single fetal heart rate determined by ultrasonography | 9-10 months after treatment | 
| Live Birth | Live Birth: delivery of a live infant; No Live Birth: no delivery of a live infant | 9-10 months after treatment | 
| Pregnancy Loss | Pregnancy Loss: any pregnancy loss including biochemical pregnancy, ectopic pregnancy, and miscarriage; No Pregnancy Loss: no pregnancy loss including biochemical pregnancy, ectopic pregnancy, or miscarriage. | 9-10 months after treatment |