Clinical trial NCT06239376: Artificial Cycle With or Without GnRH Agonist Pre-treatment for Frozen Embryo Transfer in Adenomyosis Patients
Official title: The Effectiveness of the Two Different Endometrial Preparation Regimes for Frozen Embryo Transfer in Patients With Adenomyosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Adenomyosis
IVF
Frozen Embryo Transfer
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
First posted: 2024-02-02
Enrollment: 222
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized clinical trial aims to assess the comparative effectiveness of two distinct endometrial preparation protocols for frozen embryo transfer (FET) among women with adenomyosis undergoing IVF/ICSI. Specifically, it seeks to address the following key questions:

1. Does the protocol involving the combination of GnRH agonist and letrozole for down regulation with exogenous steroids (GnRHa+AI - AC) result in a higher live birth rate compared to the use of exogenous steroids alone (AC) in women with adenomyosis undergoing frozen embryo transfer?
2. What are the common side effects of the GnRHa+AI - AC regimen?

Eligible participants will undergo screening before endometrial preparation for FET, following which they will be randomly assigned to one of two groups: GnRHa+AI - AC or AC. In the GnRHa+AI - AC group, participants will be pre-treated with GnRH agonist and letrozole two months before endometrial preparation. After this period, participants will return for endometrial preparation, and any side effects resulting from the down regulation will be evaluated. In contrast, the AC group will receive standard treatment.

Detailed description: * Adenomyosis is a benign gynecological disease in which the endometrial stroma invades the uterine myometrium. Adenomyosis affects approximately 10% of women of reproductive age. There are several hypothetical mechanisms in adenomyosis-associated infertility, including dysregulations of the myometrial architecture and function, chronic inflammation, presence of local oxygen, and altered endometrial function, which can cause implantation failure. The abnormal presence of endometrial tissue composed of glands and stroma impacts uterine smooth muscle's regular contractile function and peristalsis, resulting in menometrorrhagia, infertility, and adverse obstetric consequences. There is currently no consensus on the optimal protocol for endometrial preparation in this population, and a lack of data on this issue. Current protocols include routine protocols with or without the pre-treatment of GnRH agonist. However, it is still controversial whether GnRH agonist down-regulation can help patients with adenomyosis have better reproductive outcomes. To our knowledge, there have not been any randomized controlled trials to investigate the effectiveness of the protocols used for endometrial preparation in women with adenomyosis undergoing frozen embryo transfer.
* This will be a superiority-designed randomized clinical trial.
* This trial will be conducted at My Duc Hospital, Ho Chi Minh City, Vietnam. Potentially eligible women will be provided information about the trial as long as their stimulation cycles are initiated.
* Screening for eligibility will be performed by treating physicians on days 2nd - 4th of the menstrual cycle in the subsequent frozen embryo transfer cycles. Patients will be provided a copy of the informed consent documents. Written informed consent will be obtained from all women by the investigator before enrollment.
* Women will be randomized (1:1) to either AC (artificial cycle) or GnRHa+AI - AC (Down-Regulation with GnRH agonist and Letrozole combined with artificial cycle) protocols using block randomization with a variable block size of 4, 6, using HOPE Epi with a computer-generated random list.
* Artificial cycle (AC): the endometrium will be prepared using oral estradiol valerate (Valiera; Abbott) 6 mg/day starting from the second or fourth day of the menstrual cycle (5). The endometrial thickness will be monitored from the tenth day of estradiol-priming onwards, and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day will be initiated when endometrial thickness reaches 7 mm or more and received oestradiol valerate for at least nine days.

Embryo transfer will be scheduled by the time of the initiation of progesterone and embryo stages. Hormonal support will consist of oral estradiol valerate 4 mg/day and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day until the 7th week of gestation. Subsequently, progesterone alone (Cyclogest®; Actavis) at 400 mg twice times a day will be continued for luteal phase support until the 12th week of gestation.

- GnRH agonist + Letrozole - Artificial cycle protocol (GnRHa+AI - AC):

* Pre-treatment with GnRH agonist: GnRHa (Triptorelin - Diphereline®, Ipsen, France) will be injected at a dose of 3.75 mg on days 2nd - 4th of menstruation. In addition to GnRHa administration duration, the patients will be indicated letrozole 2.5 mg daily (Femara®, Novartis, Switzerland) to prevent the estradiol flare-up effect from the day of GnRH agonist injection. Repeat the same regimen for the second time 28 days after the first injection of GnRH agonist.
* After 55 days of Down Regulation with GnRH agonist, before starting the artificial cycle protocol for endometrial preparation, estradiol serum level will be tested before endometrial preparation.
* Endometrial preparation with AC protocol will be started 28 days after the second injection of GnRH agonist, as described previously

Frozen embryo transfer:

A maximum of 2 cleavage-stage embryos or 1 blastocyst will be thawed on the day of embryo transfer, three or five days after the start of progesterone. Two hours after thawing, surviving embryos will be transferred into the uterus under ultrasound guidance using a soft uterine catheter (Gynétics®, Belgium).

- Future babies' health evaluation and cost-effectiveness analysis will also be performed separately.

Eligibility criteria: Inclusion Criteria:

* Confirm diagnosis with adenomyosis by using transvaginal ultrasonography (MUSA consensus) and/or pelvic magnetic resonance imaging.
* Age between 18 - 42
* Undergo less or equal to three previous IVF cycles
* Indicate for frozen embryo transfer
* Agree to have not more than two day-3 embryo or one blastocyst (day-5 and day-6) transferred
* Not participating in any other study

Exclusion Criteria:

* Embryos from IVM cycle
* Having uterine or adnexal abnormalities (e.g., intrauterine adhesions, unicornuate/ bicornuate/ arcuate uterus; unremoved hydrosalpinx, endometrial polyp, submucosal leiomyoma, or leiomyoma with endometrial cavity distortion)
* Having contraindications for exogenous hormones administration: breast cancer, risks of venous thromboembolism
* Embryos from the oocyte donation cycle.
* Patients with a history of GnRH injection within three months, measured from the last GnRHa injection to the study screening date.

Primary outcomes:
measure: Live birth rate after one frozen embryo transfer cycle
timeFrame: At 22 weeks of gestation
Secondary outcomes:
measure: Cancellation rate
timeFrame: At 3 weeks from the start of artificial cycle
measure: Hypoestrogenic side effects
timeFrame: At 8 weeks from the start of the first dose of 3.75 mg GnRH agonist
measure: Classification of adenomyosis
timeFrame: during ultrasound procedure
measure: Differentiation of adenomyosis
timeFrame: during ultrasound procedure
measure: Positive pregnancy test
timeFrame: At 2 weeks after embryo placement
measure: Implantation rate
timeFrame: At 3 weeks after embryo placement
measure: Clinical pregnancy
timeFrame: At 5 weeks after embryo placement
measure: Ectopic pregnancy
timeFrame: At 7 weeks of gestation
measure: Ongoing pregnancy
timeFrame: At 10 weeks after embryo placement
measure: Miscarriage
timeFrame: before 22 completed weeks of gestational age
measure: Venous thromboembolism relating to medication
timeFrame: From the start of treatment up to 10 weeks of gestation
measure: Preterm delivery
timeFrame: At 22, 28, 32 weeks and 37 weeks of gestation
measure: Gestational diabetes mellitus
timeFrame: At 24 to 28 weeks of gestation
measure: Hypertension in pregnancy
timeFrame: after 20 weeks of gestation or beyond
measure: Major congenital abnormalities
timeFrame: At birth
measure: Birth weight
timeFrame: At the time of delivery
measure: Low birth weight
timeFrame: At the time of delivery
measure: Very low birth weight
timeFrame: At the time of delivery
measure: High birth weight
timeFrame: At the time of delivery
measure: Very high birth weight
timeFrame: At the time of delivery
measure: Admission to NICU
timeFrame: At birth
measure: Multiple pregnancy
timeFrame: At 6 to 8 weeks' gestation
measure: Multiple delivery
timeFrame: At 22 weeks' gestation
measure: Still birth
timeFrame: At 20 weeks' gestation
measure: Neonatal mortality
timeFrame: within 28 days of birth
measure: Direct costs to live birth
timeFrame: At the time of delivery
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: My Duc Hospital
Study officials:
affiliation: University of Medicine and Pharmacy at Ho Chi Minh City
name: Lan N Vuong, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020 Mar 26;382(13):1244-1256. doi: 10.1056/NEJMra1810764. No abstract available.
citation: Szubert M, Kozirog E, Olszak O, Krygier-Kurz K, Kazmierczak J, Wilczynski J. Adenomyosis and Infertility-Review of Medical and Surgical Approaches. Int J Environ Res Public Health. 2021 Jan 30;18(3):1235. doi: 10.3390/ijerph18031235.
citation: Antero MF, Ayhan A, Segars J, Shih IM. Pathology and Pathogenesis of Adenomyosis. Semin Reprod Med. 2020 May;38(2-03):108-118. doi: 10.1055/s-0040-1718922. Epub 2020 Oct 20.
citation: Mumusoglu S, Polat M, Ozbek IY, Bozdag G, Papanikolaou EG, Esteves SC, Humaidan P, Yarali H. Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review. Front Endocrinol (Lausanne). 2021 Jul 9;12:688237. doi: 10.3389/fendo.2021.688237. eCollection 2021.
citation: Zhang Y, Fu X, Gao S, Gao S, Gao S, Ma J, Chen ZJ. Preparation of the endometrium for frozen embryo transfer: an update on clinical practices. Reprod Biol Endocrinol. 2023 Jun 8;21(1):52. doi: 10.1186/s12958-023-01106-5.
citation: Harmsen MJ, Van den Bosch T, de Leeuw RA, Dueholm M, Exacoustos C, Valentin L, Hehenkamp WJK, Groenman F, De Bruyn C, Rasmussen C, Lazzeri L, Jokubkiene L, Jurkovic D, Naftalin J, Tellum T, Bourne T, Timmerman D, Huirne JAF. Consensus on revised definitions of Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis: results of modified Delphi procedure. Ultrasound Obstet Gynecol. 2022 Jul;60(1):118-131. doi: 10.1002/uog.24786.