Clinical trial NCT02912988: Letrozole in Stimulated IVF Cycles
Official title: A Randomized Trial of Letrozole as an Adjunct to Follicle Stimulating Hormone in Stimulated in Vitro Fertilization Cycles
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Subfertility
Keywords: Subfertility
In-vitro fertilization
Letrozole
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Peking University Third Hospital
First posted: 2016-09-23
Enrollment: 900
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Live birth rate
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: Miscarriage rate
timeFrame: up to 20 weeks of gestation
measure: Clinical and ongoing pregnancy rates
timeFrame: up to 20 weeks
measure: Ovarian hyperstimulation rate
timeFrame: about 1 month
measure: Total IU of FSH used per cycle
timeFrame: about 2 weeks
measure: Number of follicles > 12 mm on day of hCG (or the day before)
timeFrame: about 2 weeks
measure: Number of oocytes obtained
timeFrame: On the operation day of transvaginal ultrasound guided oocyte retrieval
measure: Proportion of oocytes resulting in top quality day 2 (or day 3) embryos according to validated morphological criteria.
timeFrame: 2-3 days after the transvaginal ultrasound guided oocyte retrieval operation
measure: Oocyte fertilization rate
timeFrame: 2-3 days after the transvaginal ultrasound guided oocyte retrieval operation
measure: Number and quality of embryos obtained
timeFrame: 2-3 days after the transvaginal ultrasound guided oocyte retrieval operation
measure: Endometrial thickness on day of hCG (or the day before)
timeFrame: on day of hCG (or the day before)
measure: Serum E2 level on day of hCG administration (or the day before)
timeFrame: on day of hCG administration (or the day before)
measure: Serum P levels on day of hCG administration (or the day before)
timeFrame: on day of hCG administration (or the day before)
measure: Serum testosterone levels on day of hCG administration (or the day before)
timeFrame: on day of hCG administration (or the day before)
measure: Follicular fluid E2 level
timeFrame: On the operation day of transvaginal ultrasound guided oocyte retrieval
measure: Follicular fluid testosterone level
timeFrame: On the operation day of transvaginal ultrasound guided oocyte retrieval
measure: Follicular fluid inhibin B level
timeFrame: On the operation day of transvaginal ultrasound guided oocyte retrieval
measure: Follicular fluid AMH level
timeFrame: On the operation day of transvaginal ultrasound guided oocyte retrieval
measure: Reported side effects
timeFrame: through study completion, an average of 1 year
measure: Complications of pregnancy
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: Hong Kong
country: China
facility: Department of Obstetrics and Gynaecology
state: Hong Kong
city: Beijing
country: China
facility: Peking University Third Hospital
Study officials:
affiliation: Department of Obstetrics and Gynaecology, The University of Hong Kong
name: Ernest HY Ng, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.