Letrozole in Stimulated IVF Cycles

Phase 3

Completed

• Conditions: Subfertility
• Interventions: Drug: Letrozole

• Registration Number: NCT02912988
• Lead Sponsor: The University of Hong Kong

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2016-09-13
• Study First Submitted QC: 2016-09-20
• Study First Posted: 2016-09-23
• Study Start: 2018-03-01
• Primary Completion: 2022-04-30
• Status Verified: 2022-11
• Study Completion: 2023-04-30
• Last Update Submitted: 2023-05-08
• Last Update Posted: 2023-05-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 900

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Letrozole group	Letrozole	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.

Primary Outcome Measures

Name	Time	Method
Live birth rate	through study completion, an average of 1 year	A baby born alive after 20 weeks gestation

Secondary Outcome Measures

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

Trial Locations

Locations (2)

Department of Obstetrics and Gynaecology; 🇨🇳 Hong Kong, Hong Kong, China

Peking University Third Hospital; 🇨🇳 Beijing, China