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Letrozole in Stimulated IVF Cycles

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ClinicalTrials.gov Identifier: NCT02912988
Recruitment Status : Recruiting
First Posted : September 23, 2016
Last Update Posted : August 20, 2020
Sponsor:
Collaborators:
University of Southampton
Peking University Third Hospital
Chinese PLA General Hospital
Information provided by (Responsible Party):
The University of Hong Kong

Tracking Information
First Submitted Date  ICMJE September 13, 2016
First Posted Date  ICMJE September 23, 2016
Last Update Posted Date August 20, 2020
Study Start Date  ICMJE November 2016
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 20, 2016)
Live birth rate [ Time Frame: through study completion, an average of 1 year ]
A baby born alive after 20 weeks gestation
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 20, 2016)
  • Miscarriage rate [ Time Frame: up to 20 weeks of gestation ]
    Miscarriage before 20 weeks gestation
  • Clinical and ongoing pregnancy rates [ Time Frame: up to 20 weeks ]
    Presence of at least one gestational sac on ultrasound at 6 weeks and 8-10 weeks
  • Ovarian hyperstimulation rate [ Time Frame: about 1 month ]
    Ovarian hyperstimulation rate classified according to Royal College of Obstetrics and Gynaecology of the United Kingdom
  • Total IU of FSH used per cycle [ Time Frame: about 2 weeks ]
    Total IU of FSH used per cycle
  • Number of follicles > 12 mm on day of hCG (or the day before) [ Time Frame: about 2 weeks ]
    Transvaginal ultrasound performed to measure and the follicles on day of hcG or the day before.
  • Number of oocytes obtained [ Time Frame: On the operation day of transvaginal ultrasound guided oocyte retrieval ]
    Number of oocyte obtained during the operation of transvaginal ultrasound guided oocyte retrieval
  • Proportion of oocytes resulting in top quality day 2 (or day 3) embryos according to validated morphological criteria. [ Time Frame: 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.
  • Oocyte fertilization rate [ Time Frame: 2-3 days after the transvaginal ultrasound guided oocyte retrieval operation ]
    Oocyte fertilization rate
  • Number and quality of embryos obtained [ Time Frame: 2-3 days after the transvaginal ultrasound guided oocyte retrieval operation ]
    Number and quality of embryos obtained
  • Endometrial thickness on day of hCG (or the day before) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: on day of hCG administration (or the day before) ]
    Hormonal profile on day of hCG administration (or the day before):serum testosterone level
  • Follicular fluid E2 level [ Time Frame: On the operation day of transvaginal ultrasound guided oocyte retrieval ]
    Follicular fluid hormonal profile: E2 level
  • Follicular fluid testosterone level [ Time Frame: On the operation day of transvaginal ultrasound guided oocyte retrieval ]
    Follicular fluid hormonal profile: testosterone level
  • Follicular fluid inhibin B level [ Time Frame: On the operation day of transvaginal ultrasound guided oocyte retrieval ]
    Follicular fluid hormonal profile: inhibin B level
  • Follicular fluid AMH level [ Time Frame: On the operation day of transvaginal ultrasound guided oocyte retrieval ]
    Follicular fluid AMH level
  • Reported side effects [ Time Frame: through study completion, an average of 1 year ]
  • Complications of pregnancy [ Time Frame: 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Letrozole in Stimulated IVF Cycles
Official Title  ICMJE A Randomized Trial of Letrozole as an Adjunct to Follicle Stimulating Hormone in Stimulated in Vitro Fertilization Cycles
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 150-300 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.

Control group:

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.

  • 150 IU HMG/FSH for women with AFC >15
  • 225 IU HMG/FSH for those with AFC 5-15
  • 300 IU HMG/FSH for those with AFC<5

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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Subfertility
Intervention  ICMJE 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 Name: Letrozole-Teva
Study Arms  ICMJE
  • 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.

    Intervention: Drug: Letrozole
  • 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.

Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 20, 2016)
900
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2021
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 42 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ernest HY Ng, MD 852-22553400 nghye@hku.hk
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02912988
Other Study ID Numbers  ICMJE UW 16-014
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party The University of Hong Kong
Study Sponsor  ICMJE The University of Hong Kong
Collaborators  ICMJE
  • University of Southampton
  • Peking University Third Hospital
  • Chinese PLA General Hospital
Investigators  ICMJE
Principal Investigator: Ernest HY Ng, MD Department of Obstetrics and Gynaecology, The University of Hong Kong
PRS Account The University of Hong Kong
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP