Letrozole in Stimulated IVF Cycles

Study Overview
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Brief Summary
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In-vitro fertilization (IVF) is the treatment of choice for couples with prolonged infertility. The treatment usually involves hormonal stimulation of the ovaries by follicle stimulating hormone (FSH), followed by surgical removal of eggs which are then mixed with sperm in the laboratory to create embryos. The success rates of IVF treatment remain unsatisfactory and are no longer increasing. One of the reasons is an adverse effect of high serum estradiol levels following FSH stimulation on the lining of the uterus. Letrozole is a drug used in the prevention of recurrence of breast cancer because of its action to reduce the intra-ovarian aromatization of androgens to estrogens. It is now increasingly used for ovulation induction and is as safe as clomiphene citrate. Use of letrozole during standard ovarian stimulation for IVF producing adequate numbers of oocytes with physiological levels of estradiol may increase the present success rate of standard IVF treatment. The aim of this randomized study is to compare the live birth rate of FSH alone versus combined FSH and letrozole used for ovarian stimulation in IVF treatment.

Detailed Description
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Trial design: Infertile women undergoing IVF treatment will be randomized into one of the following two groups by an online randomization program: Letrozole group: letrozole 2.5mg daily will be given at the start of the antagonist during ovarian stimulation i.e. day 5 of stimulation. Control group: standard care with FSH alone during ovarian stimulation. Intervention: Subjects can be put on oral contraceptive pill in the preceding cycle for scheduling stimulation. On day 2-3, a pelvic ultrasound will be performed for antral follicle count. Letrozole group: Daily 150-225 IU human menopausal gonadotrophin (HMG) / Follicle stimulating hormone (FSH) from cycle day 2-4 (at least 5 days after stopping the oral contraceptive pill) and co-treatment with letrozole 2.5 mg daily from stimulation day 5 until the day before hCG administration. GnRH antagonist (cetrotide or orgalutran) 0.25 mg daily from stimulation day 5 until the day of hCG administration. Control group: Daily 150-225 IU HMG/FSH cycle day 2-4 (at least 5 days after stopping the oral contraceptive pill) until the day before hCG administration. GnRH antagonist 0.25 mg daily from stimulation day 5 until the day of hCG administration. A blood sample will be taken and analyzed in the local laboratory for serum E2, P and testosterone levels on cycle day 2 or 3 (baseline) and day of hCG (or the day before). The remaining serum will be frozen and stored for later analysis. A sample of follicular fluid (FF) will be collected from the first blood free follicle. The FF will be frozen and stored for later analysis: Estradiol, testosterone, inhibin B and AMH levels. All techniques of IVF including harvesting of oocytes, insemination with specially prepared sperm, embryo culture in the laboratory, embryo transfer and luteal phase support will be according to local protocols. One or two embryos or blastocysts will be replaced. A pregnancy test will be carried out 2 weeks after embryo transfer in both arms. All women who have a positive pregnancy test 2 weeks after embryo transfer will undergo a transvaginal ultrasound scan to identify the presence and number of gestation sac with a fetal heart signifying an ongoing pregnancy. Pelvic scan will be repeated at 8 weeks, 12 weeks, 24 weeks and 36 weeks of gestation for fetal growth.

Official Title
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A Randomized Trial of Letrozole as an Adjunct to Follicle Stimulating Hormone in Stimulated in Vitro Fertilization Cycles

Conditions
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Subfertility

Intervention / Treatment
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* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: women under 42 years of age medical indication for IVF treatment antral follicle count prior to ovarian stimulation >=3 informed consent Exclusion Criteria: women using donor oocytes women undergoing preimplantation genetic diagnosis women with abnormal uterine cavity shown on hysterosalpingogram or saline infusion sonogram women with hydrosalpinges shown on scanning and not corrected previous documented poor response (<=3 oocytes) to ovarian stimulation using at least FSH 225 IU daily

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 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 |
| --- | --- |
| Experimental: Letrozole group<br>Letrozole + standard treatment: Daily 150-300 IU human menopausal gonadotrophin (HMG) / Follicle stimulating hormone (FSH) from cycle day 2-4 (at least 5 days after stopping the oral contraceptive pill) and co-treatment with letrozole 2.5 mg daily from stimulation day 5 until the day before hCG administration. GnRH antagonist (cetrotide or orgalutran) 0.25 mg daily from stimulation day 5 until the day of hCG administration. | Drug: Letrozole<br>* Daily 150-300 IU human menopausal gonadotrophin (HMG) / Follicle stimulating hormone (FSH) from cycle day 2-4 (at least 5 days after stopping the oral contraceptive pill) and co-treatment with letrozole 2.5 mg daily from stimulation day 5 until the day before hCG administration. GnRH antagonist (cetrotide or orgalutran) 0.25 mg daily from stimulation day 5 until the day of hCG administration.<br>* Other names: Letrozole-Teva;|
| No Intervention: Control group<br>Standard treatment: Daily 150-300 IU HMG/FSH cycle day 2-4 (at least 5 days after stopping the oral contraceptive pill) until the day before hCG administration. GnRH antagonist 0.25 mg daily from stimulation day 5 until the day of hCG administration. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth rate | A baby born alive after 20 weeks gestation | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Miscarriage rate | Miscarriage before 20 weeks gestation | up to 20 weeks of gestation | 
| Clinical and ongoing pregnancy rates | Presence of at least one gestational sac on ultrasound at 6 weeks and 8-10 weeks | up to 20 weeks | 
| Ovarian hyperstimulation rate | Ovarian hyperstimulation rate classified according to Royal College of Obstetrics and Gynaecology of the United Kingdom | about 1 month | 
| Total IU of FSH used per cycle | Total IU of FSH used per cycle | about 2 weeks | 
| Number of follicles > 12 mm on day of hCG (or the day before) | Transvaginal ultrasound performed to measure and the follicles on day of hcG or the day before. | about 2 weeks | 
| Number of oocytes obtained | Number of oocyte obtained during the operation of transvaginal ultrasound guided oocyte retrieval | On the operation day of transvaginal ultrasound guided oocyte retrieval | 
| Proportion of oocytes resulting in top quality day 2 (or day 3) embryos according to validated morphological criteria. | Proportion of oocytes resulting in top quality day 2 (or day 3) embryos according to validated morphological criteria. | 2-3 days after the transvaginal ultrasound guided oocyte retrieval operation | 
| Oocyte fertilization rate | Oocyte fertilization rate | 2-3 days after the transvaginal ultrasound guided oocyte retrieval operation | 
| Number and quality of embryos obtained | Number and quality of embryos obtained | 2-3 days after the transvaginal ultrasound guided oocyte retrieval operation | 
| Endometrial thickness on day of hCG (or the day before) | Endometrial thickness on day of hCG (or the day before) measured by transvaginal ultrasound | on day of hCG (or the day before) | 
| Serum E2 level on day of hCG administration (or the day before) | Hormonal profile on day of hCG administration (or the day before): serum E2 level | on day of hCG administration (or the day before) | 
| Serum P levels on day of hCG administration (or the day before) | Hormonal profile on day of hCG administration (or the day before): sSerum P level | on day of hCG administration (or the day before) | 
| Serum testosterone levels on day of hCG administration (or the day before) | Hormonal profile on day of hCG administration (or the day before):serum testosterone level | on day of hCG administration (or the day before) | 
| Follicular fluid E2 level | Follicular fluid hormonal profile: E2 level | On the operation day of transvaginal ultrasound guided oocyte retrieval | 
| Follicular fluid testosterone level | Follicular fluid hormonal profile: testosterone level | On the operation day of transvaginal ultrasound guided oocyte retrieval | 
| Follicular fluid inhibin B level | Follicular fluid hormonal profile: inhibin B level | On the operation day of transvaginal ultrasound guided oocyte retrieval | 
| Follicular fluid AMH level | Follicular fluid AMH level | On the operation day of transvaginal ultrasound guided oocyte retrieval | 
| Reported side effects |  | through study completion, an average of 1 year | 
| Complications of pregnancy | small for gestational age, low birth weight, preterm delivery, pre-eclampsia, antepartum haemorrhage, congenital anomaly, perinatal mortality, multiple pregnancy | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Subfertility, In-vitro fertilization, Letrozole