NATural Ovarian Stimulation (NATOS)

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

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.

Study Overview

• Status: Completed
• Conditions: Infertility
• Intervention / Treatment: Drug: Gonal-F®; Drug: Cetrotide®; Drug: Cetrotide®

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.

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Clamart, France, 92141
    • Hôpital Antoine Béclère

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

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: Control Group; 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®; 225 to 450 IU/d; from day 2 of menstrual cycle onward; Drug: Cetrotide®; 0.25 mg/day, starting on day 6 of Gonal-F®.; Drug: Cetrotide®; 1.5 mg/day (6 ampoules of 0.25 mg), starting on day 1 (S1) of Gonal-F® treatment until dhCG
Experimental: NATOS Group; 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®; 225 to 450 IU/d; from day 2 of menstrual cycle onward; Drug: Cetrotide®; 0.25 mg/day, starting on day 6 of Gonal-F®.; Drug: Cetrotide®; 1.5 mg/day (6 ampoules of 0.25 mg), starting on day 1 (S1) of Gonal-F® treatment until dhCG

What is the study measuring?

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	Time Frame
Number of oocytes obtained	At oocyte retrieval (14±8 days after start of treatment)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of embryos obtained		At day 2 of embryo development
Clinical pregnancy	Clinical pregnancy defined as pregnancy with an US-detectable gestational sac at 7 weeks of amenorrhea	7 weeks of amenorrhea
Embryo implantation	Embryo implantation defined as the total number of intrauterine gestational sacs divided by the total number of embryos transferred	7 weeks of amenorrhea
Miscarriage	Miscarriage defined as a pregnancy loss between 7 and 13 weeks of amenorrhea	Between 7 and 13 weeks of amenorrhea
"Top" quality embryo	Embryo data assessed by the number of embryos with adequate morphology	4 and 5 days after hCG administration
Blastulation	Number of cleaving embryos having reached the blastocyst stage	7 days after hCG administration
Adverse events occurring during COH	Presence of ovarian hyperstimulation syndrome (OHSS) +/- severity is measured using OHSS evaluation scale	Within the first 30 days after the start of treatment;
Gestational age at delivery		1 month post-partum
Birth weight		1 month post-partum
Pregnancy complications	antepartum haemorrhage, placental abruption, hypertensive disorders, and perinatal mortality	1 month post-partum
Patient's quality of life during COH	Fertiqol modified	At 14 days from start of treatment with cetrotide (plus or minus 8 days)
Reduced serum E2 levels on dhCG (< 800 pg/mL)	serum E2 levels will be measured from each blood sample obtained during COH	the day of hCG administration
Serum androgens levels during COH	Serum androgens levels (testosterone, SHBG, androstenedione)	Within the first 19 days after start of treatment with cetrotide (plus or minus 8 days)

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: MerckSerono Pharmaceuticals
• Investigators: Principal Investigator: RENATO FANCHIN, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2017
• Primary Completion (Actual): February 8, 2019
• Study Completion (Actual): February 8, 2019

Study Registration Dates

• First Submitted: August 25, 2016
• First Submitted That Met QC Criteria: September 1, 2016
• First Posted (Estimate): September 8, 2016

Study Record Updates

• Last Update Posted (Actual): April 30, 2021
• Last Update Submitted That Met QC Criteria: April 29, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Fertility preservation; Estradiol; Endometrial receptivity; Embryo implantation; Controlled ovarian hyperstimulation
• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Cetrorelix
• Other Study ID Numbers: P150947

Plan for Individual participant data (IPD)

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