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Does Letrozole Improve Pregnancy Outcome in Fresh Embryo Transfer IVF/ICSI Cycle? (IVF/ICSI)

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ClinicalTrials.gov Identifier: NCT03901170
Recruitment Status : Not yet recruiting
First Posted : April 3, 2019
Last Update Posted : April 10, 2019
Sponsor:
Information provided by (Responsible Party):
National Taiwan University Hospital

Tracking Information
First Submitted Date  ICMJE April 2, 2019
First Posted Date  ICMJE April 3, 2019
Last Update Posted Date April 10, 2019
Estimated Study Start Date  ICMJE April 9, 2019
Estimated Primary Completion Date April 8, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 2, 2019)
  • pregnancy rate [ Time Frame: 16 days after oocyte retrieval ]
  • implantation rate [ Time Frame: 23 days after oocyte retrieval ]
    intra-uterine gestational sac/total transfer embryo number
  • miscarriage rate [ Time Frame: gestational weeks 12 ]
    pregnancy loss before gestational weeks 12
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03901170 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 2, 2019)
live birth rate [ Time Frame: from gestational weeks 24 to 42 ]
live birth with newborn
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 2, 2019)
cumulative pregnancy rate [ Time Frame: within three months after failure to achieve pregnancy in fresh embryo transfer cycle ]
The sequential frozen-thaw embryo transfer cycle if the patient fail at fresh embryo transfer cycle
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Does Letrozole Improve Pregnancy Outcome in Fresh Embryo Transfer IVF/ICSI Cycle?
Official Title  ICMJE Does Use of Letrozole in Controlled Ovarian Stimulation in Normal Ovarian Responder in Fresh Embryo Transfer IVF/ICSI Cycle Improve the Pregnancy Rate?
Brief Summary

Letrozole (Femara), is an aromatase inhibitor which is used in the treatment of hormonally-responsive breast cancer after surgery. It is a good target for selective inhibition because estrogen production is a terminal step in the biosynthetic sequence.

Aromatase inhibitors are widely used as adjuvant endocrine therapy for postmenopausal women with breast cancer. They have been used off-label in the treatment of patients for increasing the number of ovarian follicles recruited in ovulatory women undergoing controlled ovarian hyperstimulation (COH). A shorter half-life (48 hours) which would predict a lower risk of teratogenicity. No direct antiestrogenic adverse effects on the endometrium, due to an absence of peripheral estrogen receptor blockade and the shorter half-life.

For ovarian normal responders, instead of hCG (human chorionic gonadotropin), luteal support with exogenous progesterone supplementation is the standard protocol for patients who received fresh embryo transfer for avoiding the risk of OHSS. In other normal responders who have increasing risk of OHSS, the strategy of freezing all embryos are more favored.

In previous studies, high estrogen-induced endometrial gland cells apoptosis might account for the defective endometrial receptivity in women with excessively high estrogen concentrations after ovarian hyperstimulation in IVF cycles. Since letrozole can reduce the serum level of estrogen due to its pharmacological properties, which in turn reduces the adverse effects of high estrogen on the endometrium and improve the endometrial receptivity for embryo implantation.

The investigators anticipate that infertility patients will receive short-term oral administration of letrozole (2.5 mg/tab) once a day when estrogen is elevated in the late stage of ovulation stimulation when receiving ovulation stimulation for two to three days. And transvaginal ultrasound was performed every two to three days for growth of ovarian follicles until two days before oocyte retrieval. Observing whether taking the drug can improve the maturity of the oocyte, pregnancy rate, implantation rate, miscarriage rate, ongoing pregnancy rate and live birth rate of the fresh embryo transfer cycle.

Detailed Description

Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor which is used in the treatment of hormonally-responsive breast cancer after surgery. Aromatase is a microsomal cytochrome P450 hemoprotein-containing enzyme that catalyzes the rate-limiting step in the production of estrogens: the conversion of androstenedione and testosterone via three hydroxylation steps to estrone and estradiol, respectively. It is a good target for selective inhibition because estrogen production is a terminal step in the biosynthetic sequence. Aromatase activity is present in many tissues, including the ovaries, brain, adipose tissue, muscle, liver, and breast. The investigators use letrozole as routine for patients of breast cancer who want to keep chance of fertility in the future before receiving chemotherapy which may do damage to their ovarian function. After they complete the treatment protocol of breast cancer, they can practice the fertility plan with these frozen embryos or oocytes.

Aromatase inhibitors are widely used as adjuvant endocrine therapy for postmenopausal women with breast cancer. They have been used off-label in the treatment of patients for increasing the number of ovarian follicles recruited in ovulatory women undergoing controlled ovarian hyperstimulation (COH).

A shorter half-life (48 hours) which would predict a lower risk of teratogenicity. No direct antiestrogenic adverse effects on the endometrium, due to an absence of peripheral estrogen receptor blockade and the shorter half-life. In a previous report, the addition of letrozole to gonadotropins (compared with gonadotropins alone) during IVF resulted in a greater number of oocytes and blastocysts, similar pregnancy rates, and no increased risk of ovarian hyperstimulation syndrome.

According to the current guidelines for the treatment course of IVF in NTUH (National Taiwan University Hospital), fresh embryo transfer (ET) cycle is considered for patients who have poor ovarian response because of its low risk of ovarian hyperstimulation syndrome (OHSS). Patients who have high response to ovarian stimulation with freezing all the embryos should be the best policy for avoiding high risk of OHSS and have the advantage of increasing the cumulative pregnancy rate. For ovarian normal responders, instead of hCG, luteal support with exogenous progesterone supplementation is the standard protocol for patients who received fresh embryo transfer for avoiding the risk of OHSS. In other normal responders who have increasing risk of OHSS, the strategy of freezing all embryos are more favored.

In a prospective study had shown that in the population of ovarian normal responder, the cryopreservation group has a higher clinical pregnancy rate per ET transfer (84% vs 54.7%) compared to fresh ET group. The implantation rates were 70.8% and 38.9%, respectively. The ongoing pregnancy rates per transfer (at 10 weeks' gestation) were 78.0% and 50.9%, respectively. The attributable risk percentage of implantation failure due to reduced endometrial receptivity in the fresh group was 64.7%.

The estrogen serum level is about 200~300pg/mL in a normal menstrual period. In previous studies, high estrogen-induced endometrial gland cells apoptosis might account for the defective endometrial receptivity in women with excessively high estrogen concentrations after ovarian hyperstimulation in IVF cycles. Since letrozole can reduce the serum level of estrogen due to its pharmacological properties, which in turn reduces the adverse effects of high estrogen on the endometrium and improve the endometrial receptivity for embryo implantation.

In IVF cycles, the data regarding coadministration of gonadotropins and letrozole for 5 days (days 2-6 or 3-7) in normal and high responders are quite limited. Favorable outcomes related to letrozole have been reported, including lower doses of gonadotropin consumed which decreased the cost of the IVF and increased the number of oocytes and mature oocytes while achieving the same pregnancy rate compared with conventional stimulation.

The investigators anticipate that infertility patients will receive short-term oral administration of letrozole (2.5 mg/tab) once a day when estrogen is elevated in the late stage when receiving ovulation stimulation for two to three days. Other follow-up examinations and general IVF treatments are exactly the same with control group, that is, the whole course of treatment takes about two to three days. Blood test is taken four to five times to check the concentration of hormones: including estrogen, luteinizing hormone, follicle stimulating hormone, progesterone, etc. (about 5 cc each time) And transvaginal ultrasound was performed every two to three days for growth of ovarian follicles until two days before oocyte retrieval. Observing whether taking the drug can improve the maturity of the oocyte, pregnancy rate, implantation rate, miscarriage rate, ongoing pregnancy rate and live birth rate of the fresh embryo transfer cycle.

The first endpoint of our study was to demonstrate higher implantation rates, pregnancy rates, ongoing pregnancy rates and live birth rates in the group of using letrozole. The second endpoint: the investigators want to discover the cut-off value for upper limit of estrogen serum level in fresh ET cycle which does not make significant difference in pregnancy rate between natural estrogen level and in letrozole cycle.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Compare with others who did not usage of letrozole
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Investigative Techniques
  • Reproductive Techniques
  • Reproductive Techniques, Assisted
Intervention  ICMJE Drug: Letrozole 2.5mg
oral administration of letrozole 2.5mg/tab, 1tab once per day from stimulation Day 7 to hCG Day.
Study Arms  ICMJE
  • Experimental: letrozole
    patients with letrozole
    Intervention: Drug: Letrozole 2.5mg
  • No Intervention: control
    patients without letrozole
Publications *

*   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 Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 2, 2019)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 8, 2021
Estimated Primary Completion Date April 8, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Women aged from 20 to 45 years old
  • Receive IVF treatment due to infertility
  • Plan to have fresh embryo transfer
  • Total ovarian follicle number from 8 to 15 before oocyte retrieval
  • Plan to have letrozole in IVF treatment routine

Exclusion Criteria:

  • Systemic disease, such as diabetes mellitus, hypertension, heart disease, hypothyroidism, liver or renal disease, cancer, autoimmune disease, etc.
  • Treatment cycle with pre-implantation genetic screening (PGS)/ pre-implantation genetic diagnosis(PGD)
  • Oocyte recipient
  • Poor ovarian responders according to Bologna criteria
  • Patients who have risk of Ovarian Hyperstimulation Syndrome (OHSS)
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 20 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Song-Po Pan, MD 886-2312-3456 ext 70955 ntuh105054@gmail.com
Contact: Shee-Uan Chen, Professor 886-2312-3456 ext 70950 sheeuan@ntu.edu.tw
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03901170
Other Study ID Numbers  ICMJE 201810102MINC
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Study Protocol
Responsible Party National Taiwan University Hospital
Study Sponsor  ICMJE National Taiwan University Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account National Taiwan University Hospital
Verification Date March 2019

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