Clinical trial NCT02892942: NATural Ovarian Stimulation
Official title: An Innovative Controlled Ovarian Hyperstimulation (COH) Protocol That Combines Large Oocyte Availability and Physiologic Estrogenic Environment for Good Prognosis In Vitro Fertilization and Embryo Transfer (IVF-ET) Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Infertility
Keywords: Controlled ovarian hyperstimulation
Estradiol
Embryo implantation
Endometrial receptivity
Fertility preservation
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: MerckSerono Pharmaceuticals
First posted: 2016-09-08
Enrollment: 129
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To overcome unsuitable effects of controlled ovarian hyperstimulation (COH )while maintaining large oocyte availability, investigators elaborated an innovative protocol (NATural Ovarian Stimulation) that dissociates E2 production from multiple follicle development.

The purpose of this prospective, randomized trial is to demonstrate that, in a good prognosis IVF-ET population, the physiological E2 environment resulting from NATOS significantly improves IVF-ET outcome when compared to the conventional GnRH antagonist protocol.

Detailed description: Controlled ovarian hyperstimulation (COH) seeks to improve IVF-ET results by increasing per-cycle oocyte and embryo availability. Yet, the coexistence of multiple preovulatory follicles engenders compulsory alterations in the endocrine milieu of the follicular phase. The most evident of them are the extremely high serum estradiol (E2) levels. The 10 to 15-fold increase in E2 levels as a result of COH has been shown to provoke unwanted consequences in both embryo quality and uterine receptivity.

Therefore, investigators elaborated an innovative COH protocol (NATural Ovarian Stimulation) that aimed at dissociating E2 production from multiple follicle development. To obtain this effect, they virtually curtailed endogenous LH production by using GnRH antagonist doses as strong and frequent enough to maintain E2 levels around the physiological range during standard exogenous FSH-only administration. Given that high E2 levels are commonly reached in patients having a normal follicle endowment, NATOS should target this group of good prognosis IVF-ET candidates. Indeed, this new COH approach was first tested in a pilot study that included 15 good prognosis IVF-ET candidates, aged 25-35 years, who volunteered to undergo NATOS. 11 out of 15 patients achieved a pregnancy. These pilot results spurred them to conduct a prospective, randomized trial to demonstrate that, in a good prognosis IVF-ET population, the physiological E2 environment resulting from NATOS significantly improves IVF-ET outcome when compared to the conventional GnRH antagonist protocol.

Eligibility criteria: Inclusion Criteria:

* IVF-ET candidates (excluding PGD and oocyte donor);
* Body mass index from 18 to 30 kg/m2;
* Non smokers;
* Regular menstrual cycles (25-35 days);
* Presence of both ovaries;
* Antral follicle count (follicles measuring from 3 to 10 mm in diameter) ranging from 10 to 30 on cycle days 2 to 4;
* Serum AMH levels ranging from 0.5 to 5.0 ng/mL;
* Normal endometrium at ultrasound (US) and/or hysteroscopy;
* Informed consent signed

Exclusion Criteria:

* Iatrogenic ovarian insufficiency (surgery, radiotherapy, chemotherapy);
* Uterine abnormalities as demonstrated by pelvic US and/or hysteroscopy;
* Usual contra-indications for COH (cancer risk, blood coagulation disorders, etc)
* Renal insufficiency

Primary outcomes:
measure: Live birth obtained after IVF-ET
timeFrame: 1 month post-partum
Secondary outcomes:
measure: Number of oocytes obtained
timeFrame: At oocyte retrieval (14±8 days after start of treatment)
Other outcomes:
measure: Number of embryos obtained
timeFrame: At day 2 of embryo development
measure: Clinical pregnancy
timeFrame: 7 weeks of amenorrhea
measure: Embryo implantation
timeFrame: 7 weeks of amenorrhea
measure: Miscarriage
timeFrame: Between 7 and 13 weeks of amenorrhea
measure: "Top" quality embryo
timeFrame: 4 and 5 days after hCG administration
measure: Blastulation
timeFrame: 7 days after hCG administration
measure: Adverse events occurring during COH
timeFrame: Within the first 30 days after the start of treatment;
measure: Gestational age at delivery
timeFrame: 1 month post-partum
measure: Birth weight
timeFrame: 1 month post-partum
measure: Pregnancy complications
timeFrame: 1 month post-partum
measure: Patient's quality of life during COH
timeFrame: At 14 days from start of treatment with cetrotide (plus or minus 8 days)
measure: Reduced serum E2 levels on dhCG (< 800 pg/mL)
timeFrame: the day of hCG administration
measure: Serum androgens levels during COH
timeFrame: Within the first 19 days after start of treatment with cetrotide (plus or minus 8 days)
Locations:
city: Clamart
country: France
facility: Hôpital Antoine Béclère
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: RENATO FANCHIN, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: