NATural Ovarian Stimulation

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Infertility

Intervention / Treatment
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* Drug: Gonal-F®
* Drug: Cetrotide®
* Drug: Cetrotide®


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Group<br>Background therapy which is the usual COH treatment: Recombinant FSH (Gonal-F®, 225 to 450 IU/d; MerckSerono Pharmaceuticals) from day 2 of their menstrual cycle onward, GnRH antagonist (Cetrotide®, MerckSerono Pharmaceuticals) 0.25 mg/day, S.C., starting on day 6 of Gonal-F®. | Drug: Gonal-F®<br>* 225 to 450 IU/d; from day 2 of menstrual cycle onward<br>Drug: Cetrotide®<br>* 0.25 mg/day, starting on day 6 of Gonal-F®.<br>|
| Experimental: NATOS Group<br>Background therapy which is the usual COH treatment: Recombinant FSH (Gonal-F®, 225 to 450 IU/d; MerckSerono Pharmaceuticals) from day 2 of their menstrual cycle onward, GnRH antagonist (Cetrotide®, MerckSerono Pharmaceuticals) 0.25 mg/day, S.C., starting on day 6 of Gonal-F®. GnRH antagonist treatment (Cetrotide®, MerckSerono Pharmaceuticals) will be reinforced and patients will receive 1.5 mg/day (6 ampoules of 0.25 mg), S.C., starting on day 1 (S1) of Gonal-F® treatment until dhCG | Drug: Gonal-F®<br>* 225 to 450 IU/d; from day 2 of menstrual cycle onward<br>Drug: Cetrotide®<br>* 0.25 mg/day, starting on day 6 of Gonal-F®.<br>Drug: Cetrotide®<br>* 1.5 mg/day (6 ampoules of 0.25 mg), starting on day 1 (S1) of Gonal-F® treatment until dhCG<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth obtained after IVF-ET | Live birth defined as delivery ≥ 22 weeks of amenorrhea | 1 month post-partum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of oocytes obtained |  | At oocyte retrieval (14±8 days after start of treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Controlled ovarian hyperstimulation, Estradiol, Embryo implantation, Endometrial receptivity, Fertility preservation