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

• ClinicalTrials.gov Identifier: NCT06372119
• Recruitment Status: Recruiting
• First Posted: April 17, 2024
• Last Update Posted: May 9, 2024
• Sponsor: Mỹ Đức Hospital
• Information provided by (Responsible Party): Mỹ Đức Hospital

Tracking Information

• First Submitted Date: December 27, 2023
• First Posted Date: April 17, 2024
• Last Update Posted Date: May 9, 2024
• Actual Study Start Date: April 22, 2024
• Estimated Primary Completion Date: April 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 16, 2024)

Live birth rate after one cycle of endometrial preparation [ Time Frame: After 22 completed weeks of gestational age. ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 16, 2024)

• Positive pregnancy test after one cycle of endometrial preparation [ Time Frame: At 11 days after blastocyst transfer. ]
  Defined as serum human chorionic gonadotropin level greater than 25 mIU/mL.
• Clinical pregnancy after one cycle of endometrial preparation [ Time Frame: First ultrasound before 6 weeks of gestational age. ]
  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.
• Ongoing pregnancy after one cycle of endometrial preparation [ Time Frame: After 12 weeks of gestational age. ]
  Defined as pregnancy with a detectable heart rate at 12 weeks gestation or beyond.
• Multiple pregnancy after one cycle of endometrial preparation [ Time Frame: Ultrasound at 6-9 weeks of gestational age. ]
  Defined as the presence of more than one gestational sac at early pregnancy ultrasound (6-9 weeks gestation) (Hecher and Diehl, 2009).
• Implantation rate after one cycle of endometrial preparation [ Time Frame: Ultrasound at 6-9 weeks of gestational age. ]
  A cycle in which monitoring has been initiated with the intention to treat but which did not proceed to embryo transfer (as defined above).
• Cycle cancellation rate [ Time Frame: During the intervention (on day 21 from the day of starting to use letrozole or valiera). ]
  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.
• Ectopic pregnancy rate after one cycle of endometrial preparation [ Time Frame: Ultrasound at 6-9 weeks of gestational age. ]
  A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology.
• Threatened miscarriage rate before 12 weeks of gestation after one cycle of endometrial preparation [ Time Frame: At 12 weeks of gestational age. ]
  Vaginal bleeding before 12 weeks of gestation.
• Early miscarriage rate after one cycle of endometrial preparation [ Time Frame: At 12 weeks of gestational age. ]
  Spontaneous loss of pregnancy up to 12 weeks of gestation (Oxford Textbook of Obstetrics and Gynaecology, 2020).
• Late miscarriage rate after one cycle of endometrial preparation [ Time Frame: At 22 weeks of gestational age. ]
  Spontaneous loss of pregnancy between12 to 22 weeks of gestation (Oxford Textbook of Obstetrics and Gynaecology, 2020).
• Gestational age at birth [ Time Frame: On the day of delivery. ]
  Calculated by gestational age of all live births
• Onset of labor [ Time Frame: On the day of delivery. ]
  Spontaneous, labor induction, elective C-section.
• Mode of delivery [ Time Frame: On the day of delivery. ]
  Vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor).
• Very low birth weight [ Time Frame: On the day of delivery. ]
  Birth weight less than 1500g.
• Low birth weight [ Time Frame: On the day of delivery. ]
  Birth weight less than 2500g.
• High birth weight (macrosomia) [ Time Frame: On the day of delivery. ]
  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).
• Very high birth weight (macrosomia) [ Time Frame: On the day of delivery. ]
  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).
• Gestational diabetes (GDM) [ Time Frame: At 24-28 weeks of gestational age. ]
  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).
• Hypertensive disorders of pregnancy [ Time Frame: On the day of delivery. ]
  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).
• Preterm birth [ Time Frame: On the day of delivery. ]
  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.
• Stillbirth [ Time Frame: On the day of delivery. ]
  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.
• Antepartum hemorrhage [ Time Frame: On the day of delivery. ]
  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).
• Postpartum hemorrhage [ Time Frame: On the day of delivery. ]
  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).
• Small for gestational age (singleton/twins) [ Time Frame: On the day of delivery. ]
  Small for gestational age was defined as a birth weight below the 10th percentile (de Onis and Habicht, 1996).
• Large for gestational age (singleton/twins) [ Time Frame: On the day of delivery. ]
  Large for gestational age was defined as a birth weight above the 90th percentile.
• Birth weight [ Time Frame: On the day of delivery. ]
  In grams; of singletons and twins.
• Congenital anomalies [ Time Frame: Within 28 days of birth. ]
  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.
• NICU admission [ Time Frame: Within 28 days of birth. ]
  Counting number of babies admited to neonatal intensive care unit.
• Reason for NICU admission [ Time Frame: Within 28 days of birth. ]
  Respiratory distress, intraventricular hemorrhagea, necrotizing enterocolitis, or sepsis.
• Neonatal mortality rate [ Time Frame: Within 28 days of birth. ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

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.

  Other Name: LETS
• Procedure: 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.

  Other Name: AC

Study Arms

• Active Comparator: Letrozole-stimulated cycle strategy (LETS)

  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.

  Intervention: Procedure: Letrozole-stimulated cycle strategy
• Active Comparator: Artificial cycle strategy (AC)

  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.

  Intervention: Procedure: Artificial cycle strategy

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Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 8, 2024): 790
• Original Estimated Enrollment (submitted: April 16, 2024): 480
• Estimated Study Completion Date: April 2026
• Estimated Primary Completion Date: April 2026 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 42 Years (Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Nam T Nguyen, MD.; +84354120209; bsnam.nt@myduchospital.vn

Contact: Vu NA Ho, MD.; +84935843336; bsvu.hna@myduchospital.vn

• Listed Location Countries: Vietnam

Administrative Information

• NCT Number: NCT06372119
• Other Study ID Numbers: 13/23/DD-BVMD
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Mỹ Đức Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Mỹ Đức Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Lan TN Vuong, Assoc. Prof.; University of Medicine and Pharmacy at Ho Chi Minh City

• PRS Account: Mỹ Đức Hospital
• Verification Date: May 2024