Clinical trial NCT06150703: Luteal Phase Support With GnRH Agonist After GnRH Agonist Triggering in IVF/ICSI Cycles
Official title: Luteal Phase Support With GnRH Agonist Alone After GnRH Agonist Triggering and Fresh Embryo Transfer Compared to the Reference Protocol (hCG Triggering and Progesterone Luteal Support): a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: In Vitro Fertilization
ICSI Intracytoplasmic Spermatozoid Injection
Keywords: GnRH agonist triggering
GnRH agonist luteal phase support,
pregnancy
live birth
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2023-11-29
Enrollment: 652
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 39
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The development of stimulation protocols for in vitro fertilisation (IVF) has led to a paradox. It has now been established that obtaining a large number of oocytes is a key to success, but that it is also a risk factor for embryo transfer failure after puncture (disruption of endometrial receptivity due to luteal insufficiency) and a risk factor for complications such as ovarian hyperstimulation syndrome (OHSS).

Detailed description: It is currently established that obtaining a large number of oocytes is a key of success in IVF/ICSI cycles. However, it is also a risk factor for ovarian hyperstimulation syndrome (OHSS) and a risk factor of implantation failure after fresh embryo transfer because of the alteration of endometrial receptivity. A freeze all strategy can be proposed to avoid these risks but vitrification of embryos, although more efficient than slow freezing in terms of embryo survival, is not without risk. Furthermore, proper endometrial and embryo timing for frozen-thawed embryo transfer is still debated.

Recent preliminary works suggest another possible way to combine an optimal ovarian response with the recovery of a large number of oocytes, good chances of implantation and a reduced risk of OHSS. To achieve this goal, ovulation triggering and luteal phase support need to be modified together. The human chorionic gonadotropin (hCG) (mimicking the Luteinising Hormone (LH)peak to trigger ovulation) that induces OHSS is replaced by an a GnRH agonist (GnRHa) triggering allowing an endogenous peak of Follicle Stimulating Hormone (FSH) and LH. Then, the usual support of the luteal phase by exogenous vaginal progesterone, whose absorption seems to be suboptimal for about 30% of patients, is replaced by endogenous progesterone production by the corpora lutea, supported by the maintenance of LH activity through the continuation of agonist of gonadotropin releasing hormone (AgoGnRH) in the luteal phase. Pilot studies show that a 10% to 15% increase in ongoing pregnancy rates can be expected with this type of protocol. The objective of our study is to demonstrate an increase in ongoing pregnancy rate per cycle with this new strategy combining GnRHa triggering and GnRHa luteal phase support compared to the reference protocol (hCG triggering and exogenous progesterone luteal phase support).

Eligibility criteria: Inclusion Criteria:

* Patients requiring conventional IVF or IVF with sperm injection (ICSI) from the partner or donor under the conditions of management defined by French law.
* Patients aged 18 to 39 included
* First or second attempt of IVF or ICSI
* BMI \< 35 kg/m2
* Anti-Mullerian hormone (AMH) \> 1 ng/ml (= 7 pmol/L) and/or antral follicle count ≥ 8
* AMH \< 5 ng/ml and/or antral follicle count \<40
* Treatment with recombinant FSH
* Antagonist protocol (with pre-treatment or not)
* Initial dose of recombinant FSH between 75 and 450 IU
* Signed informed consent
* Affiliation to the social security system (excluding AME)

Exclusion Criteria:

* Patient or partner with HIV, hepatitis B virus (HBV) or Hepatitis C Virus (HCV)
* ICSI with sperm from testicular biopsy
* Pre-implantation diagnosis
* Hypogonadotropic hypogonadism (amenorrhea or spaniomenorrhea with basal LH \<1.2 IU/L)
* History of severe ovarian hyperstimulation syndrome (OHSS)
* Unoperated hydrosalpinx
* Intracavitary polyps or myomas deforming the cavity
* Known hypersensitivity to the investigational drugs and/or their excipients (human chorionic gonadotropin, progesterone, nafarelin acetate, GnRH, GnRH analogues, mannitol, sodium chloride, water for injection, glacial acetic acid, Sodium hydroxide and/or hydrochloric acid, sorbitol, purified water, benzalkonium chloride, sunflower oil, soybean lecithin, gelatin, glycerol, titanium dioxide (E171), methionine, poloxamer 18, phosphoric acid).
* Gynaecological bleeding or genital haemorrhage
* Tumours of the hypothalamus or pituitary gland
* Ovarian enlargement or cysts unrelated to polycystic ovary syndrome
* Severe adenomyosis requiring a long protocol
* Carcinoma of the ovary, uterus or breast
* Active thromboembolic events
* Severe impairment of liver function
* Breastfeeding women
* Patients under court protection, guardianship or curators
* Current participation in another therapeutic interventional trial on the day of inclusion
* Patients who do not speak or understand French

Primary outcomes:
measure: Live birth, defined as the presence of a live birth after 22 weeks' gestation. Twin pregnancies will be counted as a single birth.
timeFrame: 22 weeks' gestation
Secondary outcomes:
measure: Embryo implantation defined as the presence of a gestational sac on the first ultrasound (5-8 WG)
timeFrame: 5-8 weeks' gestation
measure: Pregnancy defined as an hCG level > 10 IU/ml 14 days after oocyte retrieval.
timeFrame: 14 days after oocyte retrieval.
measure: Clinical pregnancy, defined as an intrauterine gestational sac with embryo showing cardiac activity on ultrasound at 5-10 WG
timeFrame: 5-10 weeks' gestation
measure: Miscarriage prior to 12 WG, defined as the termination of a pregnancy prior to 12 WG.
timeFrame: 12 weeks' gestation
measure: Ongoing pregnancy, defined as the presence of an intra-uterine sac with an embryo with cardiac activity visible on ultrasound between 11 weeks of gestations(WG) and 13 WG+6 days (first trimester ultrasound).
timeFrame: first trimester ultrasound (11 weeks of gestation and 13weeks of gestation +6days)
measure: Number of patients with gravidic hypertension and its onset,
timeFrame: between 12 weeks of gestation and 22 weeks of gestation
measure: Number of patients with pre-eclampsia and its onset,
timeFrame: between 12 weeks of gestation and 22 weeks of gestation
measure: Number of patients with gestational diabetes and its onset
timeFrame: between 12 weeks of gestation and 22 weeks of gestation
measure: Number of patients with term and mode of delivery
timeFrame: between 12 weeks of gestation and 22 weeks of gestation
measure: Number of patients with medical termination of pregnancy
timeFrame: between 12 weeks of gestation and 22 weeks of gestation
measure: Number of patients with late miscarriage (between 12 and 22 WG)
timeFrame: between 12 weeks of gestation and 22 weeks of gestation
measure: Number of patients with fetal death in utero
timeFrame: between 12 weeks of gestation and 22 weeks of gestation
measure: Ovarian hyperstimulation syndrome, defined as the presence of moderate to severe syndrome, early and late. Early defined as the period before D10 post retrieval and late defined as pregnancy related OHSS, after D10 post oocyte retrieval
timeFrame: before Day 10 post retrieval and after Day 10 post oocyte retrieval
measure: Progesterone levels on day of oocyte pick up and at Day 7 post oocyte pick up.
timeFrame: Day 7 post oocyte pick up
measure: Estradiol levels on day of oocyte pick up and at Day 7 post oocyte pick up.
timeFrame: Day 7 post oocyte pick up
measure: LH levels on day of oocyte pick up and at Day 7 post oocyte pick up.
timeFrame: Day 7 post oocyte pick up
measure: hCG levels on day of oocyte pick up and at Day 7 post oocyte pick up.
timeFrame: Day 7 post oocyte pick up
measure: Progesterone levels during follow-up, presence of pregnancy and presence of miscarriage.
timeFrame: 19 months
measure: Estradiol levels during follow-up, presence of pregnancy and presence of miscarriage.
timeFrame: 19 months
measure: LH levels during follow-up, presence of pregnancy and presence of miscarriage.
timeFrame: 19 months
measure: hCG levels during follow-up, presence of pregnancy and presence of miscarriage.
timeFrame: 19 months
measure: All adverse events up to delivery
timeFrame: 19 months
measure: Number of oocytes collected,
timeFrame: oocyte puncture visit
measure: number of mature oocytes
timeFrame: oocyte puncture visit
measure: number of oocytes fertilised,
timeFrame: 5th day post oocyte puncture visit
measure: number of embryos on the second day of development,
timeFrame: 5th day post oocyte puncture visit
measure: number of blastocysts obtained,
timeFrame: 5th day post oocyte puncture visit
measure: number of blastocysts transferred,
timeFrame: 5th day post oocyte puncture visit
measure: number of blastocysts frozen.
timeFrame: 5th day post oocyte puncture visit
Other outcomes:
Locations:
city: Bondy
country: France
facility: Maeliss Peigné
Study officials:
References: