Letrozole-stimulated Cycle Strategy Versus Artificial Cycle Strategy (LETSACT)

Embryo Transfer Clinical Trial

Official title:

Letrozole-stimulated Cycle Strategy Versus Artificial Cycle Strategy for Endometrial Preparation in Women With Irregular Menstrual Cycles: A Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06372119
• Other study ID #: 13/23/DD-BVMD
• Status: Recruiting
• Phase: N/A
• Start date: April 22, 2024
• Est. completion date: April 2026

Study information

• Verified date: May 2024
• Source: M? Ð?c Hospital
• Contact: Nam T Nguyen, MD.
• Phone: +84354120209
• Email: bsnam.nt[@]myduchospital.vn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this randomized clinical trial is to evaluate the effectiveness of the letrozole-stimulated cycle strategy versus the artificial cycle strategy for endometrial preparation in women with irregular menstrual cycles after one cycle of endometrial preparation. The primary question it aims to answer is:

• Does the letrozole-stimulated cycle strategy for endometrial preparation result in a higher live birth rate compared to the artificial cycle strategy in women with irregular menstrual cycles after one cycle of endometrial preparation?

Participants will undergo screening before endometrial preparation for frozen embryo transfer, following which they will be randomly assigned to one of two groups: LETS or AC. In the LETS group, investigators will prescribe letrozole 5 milligrams/day for 5 days to stimulate follicular development and micronized progesterone 800 milligrams/day for luteal phase support. In contrast, the AC group will receive oral estradiol valerate 6-12 milligrams/day and micronized progesterone 800 milligrams/day. Researchers will compare the LETS and AC groups to determine if there are differences in live birth rates.

Description:

Freeze-all and later frozen embryo transfer (FET) to reduce the risk of ovarian hyperstimulation syndrome (OHSS) is a common strategy in modern assisted reproduction technology (ART). Preparing the endometrium for FET in women with irregular menstrual cycles poses a challenge due to limited protocol options. There are two basic endometrial preparation regimens before FET: artificial cycle (AC) or natural cycle (NC). NC is often only considered if the woman has regular ovulation. In women with irregular menstrual cycles, the most popular conventional technique of endometrial preparation is AC. The advantages of AC include its convenience (meaning that the window of implantation can be determined actively and correctly) and its adaptability (meaning that the duration and the dose of exposure to estradiol and progesterone hormones can be flexibly scheduled). On the other hand, artificial exogenous estradiol levels may diminish endometrial receptivity, increase the risk of thrombosis and cancer, and negatively impact the baby's outcomes. Furthermore, the absence of the corpus luteum and its products in early pregnancy may be associated with an increased risk of placentation deficiency and an increased risk of (pre)eclampsia, which is already common in this population.

The current modern approach in endometrial preparation is to create the endometrial proliferative phase that mimics the NC's physiology and to attempt to produce the corpus luteum. Previous studies showed that in the general population, ovulation-based cycles resulted in considerably greater pregnancy rates than AC, regardless of whether ovulation was natural or inducted. Exogenous gonadotropins, clomiphene citrate (CC), and aromatase inhibitors (AI) are the three types of ovulation-inducing agents widely utilized for women with irregular menstrual periods. Gonadotropin is not patient-friendly due to the route of administration and increases the risk of OHSS. CC is well-known for its antagonistic effect on estrogen receptors and its negative impact on endometrial receptivity. Letrozole, a preferred drug in the AI group, has been explored for almost two decades to avoid the drawbacks of other methods. First, letrozole can stimulate mono-follicular growth and minimize the incidence of OHSS at a low cost and in a more patient-friendly manner. Second, letrozole decreases intraovarian and serum estrogen levels, thereby upregulating endometrial estrogen receptors, increasing endometrial sensitivity to estrogen increase, and preventing premature progesterone action, which results in increased endometrial proliferation. Thirdly, there was evidence that letrozole may improve endometrial receptivity by modulating the formation of αvβ3 and HOXA10 integrin, leukemia inhibitory factor (LIF), L-selectin, and pinopode formation.

The findings of some previous studies showed that the letrozole-stimulated cycle was superior to AC in terms of improving clinical pregnancy rate, live birth rate, and lower risk of miscarriage, preterm birth, pre-ecclampisa and also decreasing the risk of ectopic pregnancy. However, there was also evidence that shows no consistent advantage of letrozole as compared to AC. Notably, prior research on the effectiveness of letrozole in endometrial preparation for FET was predominantly retrospective. There were few randomized controlled trials (RCT) comparing the letrozole-stimulated cycle versus AC. However, these studies found similar treatment outcomes with two endometrial preparation methods. The sample size was also limited (N < 150), and letrozole was often used in combination with hMG concurrently.

This study will be undertaken at IVFMD, a reproductive center of My Duc Hospital in Ho Chi Minh City, Vietnam, to provide evidence on how effective letrozole is compared to conventional AC.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 790
• Est. completion date: April 2026
• Est. primary completion date: April 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 42 Years

Eligibility

Inclusion Criteria:

• Aged between 18 - 42.

• Irregular menstrual cycle (< 21 days or > 35 days or < 8 cycles/years).

• Indicated for endometrial preparation.

• Transfer of only one blastocyst.

• Not participating in any other trials.

Exclusion Criteria:

• Allergy to letrozole or Ovitrelle or oral estradiol valerate or micronized progesterone

• Having embryos from either oocyte donation or PGT (pre-implantation genetics testings) cycles.

• Ovarian cysts that are unrelated to the oocyte pick-up.

• Confirmed diagnosis with recurrent pregnancy loss (RPL) according to ESHRE guideline 2023, recurrent implantation failure (RIF) according to ESHRE 2023 good practice recommendations.

• Endometrial abnormalities include endometrial hyperplasia, intrauterine adhesions, endometrial polyp, and chronic endometritis.

• Uterine abnormalities include leiomyomas L0, L1, or L2 (according to FIGO 2011); adenomyosis (according to MUSA 2022); congenital uterine abnormalities, include didelphus, arcuate, unicornuate, bicornuate, septate (according to ASRM 2021).

• Untreated hydrosalpinx.

Related Conditions & MeSH terms

• Embryo Transfer
• Hormone Replacement Therapy
• Letrozole
• Menstruation Disturbances

Intervention

Procedure:
• Letrozole-stimulated cycle strategy
Letrozole (Femara® 2.5 milligrams, Novartis, Switzerland or Lezra® 2.5 milligrams, Actavis, Rumani) 5 milligrams/day for 5 days, starting on the second to fourth day of the menstrual cycle. Post-letrozole, ultrasound checks follicle growth. If =18mm, Ovitrelle® 250 mcg (Merck, Kenilworth, New Jersey, USA) induces ovulation. Luteal phase support with vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day starting two days post-hCG. Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and =7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day. Cycle cancellation criteria: no follicle development on day 21 from the day of starting letrozole, spontaneous ovulation, letrozole intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome.
• Artificial cycle strategy
Oral estradiol valerate (Progynova® 2 milligrams, Bayer Pharma AG, Germany or Valiera® 2 milligrams, Laboratories Recalcine, Chile) 6 milligrams/day for 10 days, starting on the second to fourth day of the menstrual cycle. Post-estradiol, ultrasound checks endometrial thickness. If =7mm, start vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day. If <7mm, increase the dose of oral estradiol valerate to 8 milligrams/day (5-6 days) and 12 milligrams/day (5-6 days). Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and =7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day. Cycle cancellation criteria: endometrial thickness <7mm on day 21 of using estradiol, spontaneous ovulation, oral estradiol valerate intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome.

Locations

Country	Name	City	State
Vietnam	My Duc Hospital	Ho Chi Minh City
Vietnam	My Duc Phu Nhuan Hospital	Ho Chi Minh City

Sponsors (1)

Lead Sponsor	Collaborator
M? Ð?c Hospital

Country where clinical trial is conducted

Vietnam, 

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* Note: There are 53 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Live birth rate after one cycle of endometrial preparation	Live birth will be defined as the complete expulsion or extraction from a woman of a product of fertilization, after 22 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is atached. A birth weight of 500 grams or more can be used if gestational age is unknown. Twin and higher multiple births will be reported as a single live birth event.	After 22 completed weeks of gestational age.
Secondary	Positive pregnancy test after one cycle of endometrial preparation	Defined as serum human chorionic gonadotropin level greater than 25 mIU/mL.	At 11 days after blastocyst transfer.
Secondary	Clinical pregnancy after one cycle of endometrial preparation	Diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy at 6 weeks or more after the onset of last menstrual period. In addition to intra-uterine pregnancy, it includes a clinically documented ectopic pregnancy.	First ultrasound before 6 weeks of gestational age.
Secondary	Ongoing pregnancy after one cycle of endometrial preparation	Defined as pregnancy with a detectable heart rate at 12 weeks gestation or beyond.	After 12 weeks of gestational age.
Secondary	Multiple pregnancy after one cycle of endometrial preparation	Defined as the presence of more than one gestational sac at early pregnancy ultrasound (6-9 weeks gestation) (Hecher and Diehl, 2009).	Ultrasound at 6-9 weeks of gestational age.
Secondary	Implantation rate after one cycle of endometrial preparation	A cycle in which monitoring has been initiated with the intention to treat but which did not proceed to embryo transfer (as defined above).	Ultrasound at 6-9 weeks of gestational age.
Secondary	Cycle cancellation rate	A cycle in which monitoring has been initiated with the intention to treat but which did not proceed to embryo transfer due to the criteria defined above or protocol violation.	During the intervention (on day 21 from the day of starting to use letrozole or valiera).
Secondary	Ectopic pregnancy rate after one cycle of endometrial preparation	A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology.	Ultrasound at 6-9 weeks of gestational age.
Secondary	Threatened miscarriage rate before 12 weeks of gestation after one cycle of endometrial preparation	Vaginal bleeding before 12 weeks of gestation.	At 12 weeks of gestational age.
Secondary	Early miscarriage rate after one cycle of endometrial preparation	Spontaneous loss of pregnancy up to 12 weeks of gestation (Oxford Textbook of Obstetrics and Gynaecology, 2020).	At 12 weeks of gestational age.
Secondary	Late miscarriage rate after one cycle of endometrial preparation	Spontaneous loss of pregnancy between12 to 22 weeks of gestation (Oxford Textbook of Obstetrics and Gynaecology, 2020).	At 22 weeks of gestational age.
Secondary	Gestational age at birth	Calculated by gestational age of all live births	On the day of delivery.
Secondary	Onset of labor	Spontaneous, labor induction, elective C-section.	On the day of delivery.
Secondary	Mode of delivery	Vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor).	On the day of delivery.
Secondary	Very low birth weight	Birth weight less than 1500g.	On the day of delivery.
Secondary	Low birth weight	Birth weight less than 2500g.	On the day of delivery.
Secondary	High birth weight (macrosomia)	Implies growth beyond an absolute birth weight, historically 4000 g or 4500 g, regardless of the gestational age ("Macrosomia: ACOG Practice Bulletin, Number 216," 2020).	On the day of delivery.
Secondary	Very high birth weight (macrosomia)	Birth weight over than 4500 g for women with diabetes, and a threshold of 5000 g for women without diabetes ("Macrosomia: ACOG Practice Bulletin, Number 216," 2020).	On the day of delivery.
Secondary	Gestational diabetes (GDM)	Diagnosed according to the latest version of ADA guidelines: a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and 2 h, at 24-28 weeks of gestation in women not previously diagnosed with diabetes; fasting: 92 mg/dL (5.1 mmol/L); 1h: 180 mg/dL (10.0 mmol/L); 2h: 153 mg/dL (8.5 mmol/L).	At 24-28 weeks of gestational age.
Secondary	Hypertensive disorders of pregnancy	Comprising pregnancy-induced hypertension (PIH), pre-eclampsia/eclampsia and Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. PIH diagnosed after 20 weeks' gestation; systolic blood pressure =140 mmHg or diastolic pressure =90 mmHg on two occasions, two hours apart, or severely elevated single blood pressure measurement requiring an hypertensive medication. Pre-eclampsia/eclampsia diagnosed according to ACOG practice bulletin (ACOG Committee on Obstetric Practice, 2002). Diagnosis and management of preeclampsia and eclampsia. HELLP syndrome is defined as a condition with the clinical presentation of hemolysis, elevated liver enzymes, and low platelet count; lactate dehydrogenase (LDH) elevated to 600 IU/L or more, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevated more than twice the upper limit of normal, and the platelets count less than 100000 × 10^9/L (ACOG Committee on Obstetric Practice, 2002).	On the day of delivery.
Secondary	Preterm birth	Defined as delivery at <24, <28, <32, <37 completed weeks. A birth that takes place after 22 weeks and before 37 completed weeks of gestational age.	On the day of delivery.
Secondary	Stillbirth	The death of a fetus prior to the complete expulsion or extraction from its mother after 28 completed weeks of gestational age. The death will be determined by the fact that, after such separation, the fetus does not breathe or show any other evidence of life, such as heartbeat, umbilical cord pulsation, or definite movement of voluntary muscles. Note: It includes deaths occurring during labor.	On the day of delivery.
Secondary	Antepartum hemorrhage	Defined as bleeding from or into the genital tract, occurring from 24 weeks of pregnancy and prior to the birth of the baby (Royal College of Obstetricians and Gynaecologists, 2011).	On the day of delivery.
Secondary	Postpartum hemorrhage	Defines as cumulative blood loss greater than or equal to 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process (includes intrapartum loss) regardless of route of delivery (Committee on Practice Bulletins-Obstetrics, 2017).	On the day of delivery.
Secondary	Small for gestational age (singleton/twins)	Small for gestational age was defined as a birth weight below the 10th percentile (de Onis and Habicht, 1996).	On the day of delivery.
Secondary	Large for gestational age (singleton/twins)	Large for gestational age was defined as a birth weight above the 90th percentile.	On the day of delivery.
Secondary	Birth weight	In grams; of singletons and twins.	On the day of delivery.
Secondary	Congenital anomalies	Structural or functional disorders that occur during intra-uterine life and can be identified prenatally, at birth, or later in life. Congenital anomalies can be caused by single gene defects, chromosomal disorders, multifactorial inheritance, environmental teratogens, and micronutrient deficiencies. The time of identification should be reported.	Within 28 days of birth.
Secondary	NICU admission	Counting number of babies admited to neonatal intensive care unit.	Within 28 days of birth.
Secondary	Reason for NICU admission	Respiratory distress, intraventricular hemorrhagea, necrotizing enterocolitis, or sepsis.	Within 28 days of birth.
Secondary	Neonatal mortality rate	Death of a live-born baby within 28 days of birth. This can be divided into early neonatal mortality, if death occurs in the first seven days after birth, and late neonatal if death occurs between eight and 28 days after delivery.	Within 28 days of birth.