NATural Ovarian Stimulation (NATOS)

March 30, 2026 updated by: Assistance Publique - Hôpitaux de Paris

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
129

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 36 years (Adult)

Accepts Healthy Volunteers

No

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Live birth obtained after IVF-ET
Time Frame: 1 month post-partum
Live birth defined as delivery ≥ 22 weeks of amenorrhea
1 month post-partum

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Number of oocytes obtained
Time Frame: At oocyte retrieval (14±8 days after start of treatment)
At oocyte retrieval (14±8 days after start of treatment)

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of embryos obtained
Time Frame: At day 2 of embryo development
At day 2 of embryo development
Clinical pregnancy
Time Frame: 7 weeks of amenorrhea
Clinical pregnancy defined as pregnancy with an US-detectable gestational sac at 7 weeks of amenorrhea
7 weeks of amenorrhea
Embryo implantation
Time Frame: 7 weeks of amenorrhea
Embryo implantation defined as the total number of intrauterine gestational sacs divided by the total number of embryos transferred
7 weeks of amenorrhea
Miscarriage
Time Frame: Between 7 and 13 weeks of amenorrhea
Miscarriage defined as a pregnancy loss between 7 and 13 weeks of amenorrhea
Between 7 and 13 weeks of amenorrhea
"Top" quality embryo
Time Frame: 4 and 5 days after hCG administration
Embryo data assessed by the number of embryos with adequate morphology
4 and 5 days after hCG administration
Blastulation
Time Frame: 7 days after hCG administration
Number of cleaving embryos having reached the blastocyst stage
7 days after hCG administration
Adverse events occurring during COH
Time Frame: Within the first 30 days after the start of treatment;
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
Time Frame: 1 month post-partum
1 month post-partum
Birth weight
Time Frame: 1 month post-partum
1 month post-partum
Pregnancy complications
Time Frame: 1 month post-partum
antepartum haemorrhage, placental abruption, hypertensive disorders, and perinatal mortality
1 month post-partum
Patient's quality of life during COH
Time Frame: At 14 days from start of treatment with cetrotide (plus or minus 8 days)
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)
Time Frame: the day of hCG administration
serum E2 levels will be measured from each blood sample obtained during COH
the day of hCG administration
Serum androgens levels during COH
Time Frame: Within the first 19 days after start of treatment with cetrotide (plus or minus 8 days)
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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Assistance Publique - Hôpitaux de Paris

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
URC-CIC Paris Descartes Necker Cochin
MerckSerono Pharmaceuticals

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: RENATO FANCHIN, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 13, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 8, 2019

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 8, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 25, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 1, 2016

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 8, 2016

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 3, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 30, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • P150947

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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