Clinical trial NCT06372119: Letrozole-stimulated Cycle Strategy Versus Artificial Cycle Strategy (LETSACT)
Official title: Letrozole-stimulated Cycle Strategy Versus Artificial Cycle Strategy for Endometrial Preparation in Women With Irregular Menstrual Cycles: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Embryo Transfer
Irregular Menstruation
Letrozole
Hormone Replacement Therapy
Keywords: Blastocyst Transfer
Irregular Menstruation
Letrozole
Hormone Replacement Therapy
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
First posted: 2024-04-17
Enrollment: 790
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Live birth rate after one cycle of endometrial preparation
timeFrame: After 22 completed weeks of gestational age.
Secondary outcomes:
measure: Positive pregnancy test after one cycle of endometrial preparation
timeFrame: At 11 days after blastocyst transfer.
measure: Clinical pregnancy after one cycle of endometrial preparation
timeFrame: First ultrasound before 6 weeks of gestational age.
measure: Ongoing pregnancy after one cycle of endometrial preparation
timeFrame: After 12 weeks of gestational age.
measure: Multiple pregnancy after one cycle of endometrial preparation
timeFrame: Ultrasound at 6-9 weeks of gestational age.
measure: Implantation rate after one cycle of endometrial preparation
timeFrame: Ultrasound at 6-9 weeks of gestational age.
measure: Cycle cancellation rate
timeFrame: During the intervention (on day 21 from the day of starting to use letrozole or valiera).
measure: Ectopic pregnancy rate after one cycle of endometrial preparation
timeFrame: Ultrasound at 6-9 weeks of gestational age.
measure: Threatened miscarriage rate before 12 weeks of gestation after one cycle of endometrial preparation
timeFrame: At 12 weeks of gestational age.
measure: Early miscarriage rate after one cycle of endometrial preparation
timeFrame: At 12 weeks of gestational age.
measure: Late miscarriage rate after one cycle of endometrial preparation
timeFrame: At 22 weeks of gestational age.
measure: Gestational age at birth
timeFrame: On the day of delivery.
measure: Onset of labor
timeFrame: On the day of delivery.
measure: Mode of delivery
timeFrame: On the day of delivery.
measure: Very low birth weight
timeFrame: On the day of delivery.
measure: Low birth weight
timeFrame: On the day of delivery.
measure: High birth weight (macrosomia)
timeFrame: On the day of delivery.
measure: Very high birth weight (macrosomia)
timeFrame: On the day of delivery.
measure: Gestational diabetes (GDM)
timeFrame: At 24-28 weeks of gestational age.
measure: Hypertensive disorders of pregnancy
timeFrame: On the day of delivery.
measure: Preterm birth
timeFrame: On the day of delivery.
measure: Stillbirth
timeFrame: On the day of delivery.
measure: Antepartum hemorrhage
timeFrame: On the day of delivery.
measure: Postpartum hemorrhage
timeFrame: On the day of delivery.
measure: Small for gestational age (singleton/twins)
timeFrame: On the day of delivery.
measure: Large for gestational age (singleton/twins)
timeFrame: On the day of delivery.
measure: Birth weight
timeFrame: On the day of delivery.
measure: Congenital anomalies
timeFrame: Within 28 days of birth.
measure: NICU admission
timeFrame: Within 28 days of birth.
measure: Reason for NICU admission
timeFrame: Within 28 days of birth.
measure: Neonatal mortality rate
timeFrame: Within 28 days of birth.
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: My Duc Hospital
city: Ho Chi Minh City
country: Vietnam
facility: My Duc Phu Nhuan Hospital
Study officials:
affiliation: University of Medicine and Pharmacy at Ho Chi Minh City
name: Lan TN Vuong, Assoc. Prof.
role: PRINCIPAL_INVESTIGATOR
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