Letrozole in Stimulated IVF Cycles

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

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.

Study Overview

• Status: Completed
• Conditions: Subfertility
• Intervention / Treatment: Drug: Letrozole

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 Type: Interventional
• Enrollment (Actual): 900
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100191
    • Peking University Third Hospital
  • Hong Kong
    • Hong Kong, Hong Kong, China
      • Department of Obstetrics and Gynaecology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 42 years (Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Letrozole group; 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; 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.; Other Names: Letrozole-Teva
No Intervention: Control group; 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?

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

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: Peking University Third Hospital
• Investigators: Principal Investigator: Ernest HY Ng, MD, Department of Obstetrics and Gynaecology, The University of Hong Kong

Publications and helpful links

General Publications

• Guo W, Li HWR, Yang Z, Zeng L, Yang R, Qiao J, Li R, Ng EHY. Live birth after letrozole as an adjunct to follicle-stimulating hormone versus follicle-stimulating hormone alone for ovarian stimulation in in vitro fertilisation cycles-study protocol for a randomised controlled trial. Trials. 2022 Apr 1;23(1):247. doi: 10.1186/s13063-022-06185-0.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Actual): April 30, 2022
• Study Completion (Actual): April 30, 2023

Study Registration Dates

• First Submitted: September 13, 2016
• First Submitted That Met QC Criteria: September 20, 2016
• First Posted (Estimate): September 23, 2016

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: In-vitro fertilization; Letrozole; Subfertility
• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: UW 16-014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No