Artificial Cycle With or Without GnRH Agonist Pre-treatment for Frozen Embryo Transfer in Adenomyosis Patients (FET-ADE)

The Effectiveness of the Two Different Endometrial Preparation Regimes for Frozen Embryo Transfer in Patients With Adenomyosis

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.

Study Overview

• Status: Recruiting
• Conditions: Adenomyosis; Frozen Embryo Transfer; IVF
• Intervention / Treatment: Procedure: GnRHa+AI - AC; Procedure: Artificial cycle

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.

• Study Type: Interventional
• Enrollment (Estimated): 222
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Vu NA Ho, MD; Phone Number: +84935843336; Email: bsvu.hna@myduchospital.vn
• Study Contact Backup: Name: Tien K Le, MD; Phone Number: +84962803875; Email: bstien.lk@myduchospital.vn

Study Locations

• Vietnam
  • Ho Chi Minh City, Vietnam, 70000
    • Recruiting
    • My Duc Hospital
    • Contact: Tuong M Ho, MSc, MD; Phone Number: +84 90 3633377; Email: tuongho.ivfmd@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Confirm diagnosis with adenomyosis by using transvaginal ultrasonography (MUSA consensus) and/or pelvic magnetic resonance imaging with a uterine DAP of less than 60mm on a 2-D ultrasound scan.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GnRH agonist + Letrzole - Artificial Cycle; Pre-treatment includes two doses of 3.75 mg GnRH agonist (Diphereline®, Ipsen, France) on days 2-4 of the menstrual cycle and 28 days later, along with daily 2.5 mg Letrozole (Femara®, Novartis, Switzerland) starting from the first agonist injection. Endometrial preparation in an artificial cycle begins 28 days after the second agonist injection. Patients will take 6 mg/day of oral estradiol valerate (Valiera; Abbott) at least 9 days before initiating progesterone. Endometrial thickness is monitored starting on the 10th day. When it reaches ≥7 mm, 400 mg twice times a day of vaginal progesterone (Cyclogest®, Actavis, UK) is initiated. Embryo transfer aligns with progesterone initiation, taking the embryo's stage into account. Luteal phase support comprises oral estradiol valerate 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA.	Procedure: GnRHa+AI - AC; Pre-treatment includes two doses of 3.75 mg GnRH agonist (Diphereline®, Ipsen, France) on days 2-4 of the menstrual cycle and 28 days later, along with daily 2.5 mg Letrozole (Femara®, Novartis, Switzerland) starting from the first agonist injection. Endometrial preparation in an artificial cycle begins 28 days after the second agonist injection. Patients take 6 mg/day of oral estradiol valerate (Valiera; Abbott) at least 9 days before progesterone. Endometrial thickness is monitored starting on the 10th day. When it reaches ≥7 mm, 400 mg twice times a day of vaginal progesterone (Cyclogest®, Actavis, UK) is initiated. Embryo transfer aligns with progesterone initiation, taking the embryo's stage into account. Luteal phase support comprises oral estradiol valerate 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA.; Other Names: DR-AC
Active Comparator: Artificial Cycle; The endometrium will be prepared using oral estradiol valerate (Valiera; Abbott) 6 mg/day starting from the 2nd to the 4th day of the menstrual cycle. The endometrial thickness will be monitored from day 10th onwards, and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day will be initiated when endometrial thickness reaches ≥7 mm. Estradiol exposure must last for at least 9 days before progesterone administration. Embryo transfer will be scheduled by the time of the initiation of progesterone and embryo stages. Luteal phase support comprises oral estradiol valerate 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA.	Procedure: Artificial cycle; The endometrium will be prepared using oral estradiol valerate (Valiera; Abbott) 6 mg/day starting from the 2nd to the 4th day of the menstrual cycle. The endometrial thickness will be monitored from day 10th onwards, and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day will be initiated when endometrial thickness reaches ≥7 mm. Estradiol exposure must last for at least 9 days before progesterone administration. Embryo transfer will be scheduled by the time of the initiation of progesterone and embryo stages. Luteal phase support comprises estradiol 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA.; Other Names: AC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth rate after one frozen embryo transfer cycle	Live birth is 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 attached. A birth weight of 500 grams or more can be used if gestational age is unknown	At 22 weeks of gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive pregnancy test	Serum ß-hCG ≥25mIU/mL	At 2 weeks after embryo placement
Birth weight	Weight of singletons and twins	At the time of delivery
Admission to NICU	The admittance of the newborn to NICU	At birth
Preterm delivery	Multiple definitions, defined as delivery at <24, <28, <32, <37 completed weeks	At 22, 28, 32 weeks and 37 weeks of gestation
Venous thromboembolism relating to medication	Venous thromboembolism is diagnosed after clinical examination, ultrasound scan and blood test	From the start of treatment up to 10 weeks of gestation
Still birth	The death of a fetus prior to the complete expulsion or extraction from its mother after 20 completed weeks of gestational age. The death is 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.	At 20 weeks' gestation
Cancellation rate	Cancellation due to: thin endometrium (thickness <7mm after ≥21 days using oral estradiol valerate), endometrial cavity fluid, functional cyst (homogeneous anechoic cyst with d ≥14 mm present after 10 days using estradiol valerate), or has side effects(Cluster headache, mood swing, abnormal uterine bleeding, nausea, vomit, VTE, stroke)	At 3 weeks from the start of artificial cycle
Implantation rate	Implantation rate is explained as the number of gestational sacs per number of embryos transferred.	At 3 weeks after embryo placement
Clinical pregnancy	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 the last menstrual period. In addition to intra-uterine pregnancy, it includes a clinically documented ectopic pregnancy.	At 5 weeks after embryo placement
Ectopic pregnancy	A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualisation, or histopathology	At 7 weeks of gestation
Ongoing pregnancy	Having at least one gestational sac on ultrasound at 12 weeks' gestation with heart beat activity	At 10 weeks after embryo placement
Miscarriage	The spontaneous loss of an intra-uterine pregnancy before 22 completed weeks of gestational age	before 22 completed weeks of gestational age
Gestational diabetes mellitus	GDM is diagnosed using a 75g oral glucose tolerance test	At 24 to 28 weeks of gestation
Hypertension in pregnancy	Pregnancy-induced hypertension, pre-eclampsia, eclampsia and HELLP syndrome	after 20 weeks of gestation or beyond
Major congenital abnormalities	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. Any congenital anomaly will be included as followed definition of congenital abnormalities in Surveillance of Congenital Anomalies by Division of Birth Defects and Developmental Disabilities, NCBDDD, Centers for Disease Control and Prevention (2020).	At birth
Low birth weight	Weight < 2500 gm at birth	At the time of delivery
Very low birth weight	Weight < 1500 gm at birth	At the time of delivery
High birth weight	Weight 4000 gm or 4500 gm at birth	At the time of delivery
Very high birth weight	Weight over than 4.500 g for women with diabetes, and a threshold of 5000 g for women without diabetes	At the time of delivery
Multiple pregnancy	≥2 gestational sac at early pregnancy ultrasound	At 6 to 8 weeks' gestation
Multiple delivery	Birth of more than one baby beyond 22 weeks	At 22 weeks' gestation
Neonatal mortality	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
Direct costs to live birth	Total direct cost to have a live birth after embryo transfer. Direct cost include medical consultations, ovulation stimulation drugs, laboratory and embryology services, ultrasound scanning, medical procedures such as oocyte retrieval and embryo transfer, hospital charges, nursing and counselling services and administrative and overhead charges (Mark P. Connolly et al., 2010). Cost data will be collected for a supplementary analysis and will be reported in a separated paper.	At the time of delivery
Hypoestrogenic side effects	Side effects include hot flushes, bone loss, vaginal dryness, decreased libido, unpredictable mood changes, and headache.	At 8 weeks from the start of the first dose of 3.75 mg GnRH agonist
Classification of adenomyosis	The classification of adenomyosis under ultrasound scan according to MUSA criteria	during ultrasound procedure
Differentiation of adenomyosis	The differentiation of adenomyosis under ultrasound scan according to MUSA criteria	during ultrasound procedure

Collaborators and Investigators

• Sponsor: Mỹ Đức Hospital
• Investigators: Principal Investigator: Lan N Vuong, MD, PhD, University of Medicine and Pharmacy at Ho Chi Minh City

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2024
• Primary Completion (Estimated): January 15, 2026
• Study Completion (Estimated): January 2, 2027

Study Registration Dates

• First Submitted: December 18, 2023
• First Submitted That Met QC Criteria: January 25, 2024
• First Posted (Actual): February 2, 2024

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Adenomyosis
• Other Study ID Numbers: 12/23/DD-BVMD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No