Effect of Different Ovarian Stimulation Protocols on Endometrial Receptivity

May 31, 2023 updated by: Instituto Valenciano de Infertilidade de Lisboa

How do Different Ovarian Stimulation Protocols Affect Endometrial Receptivity During a Fresh In-vitro Fertilization Attempt

This study will assess the change in endometrial gene expression signature on the day of embryo transfer according to the type of exogenous gonadotropins administered.

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

Late-follicular elevated progesterone (LFEP) following ovarian stimulation for assisted reproductive technologies (ART) has been linked to abnormal endometrial receptivity expression profiles and lower pregnancy rates. For this reason, physicians frequently propose that patients with LFEP avoid performing a fresh embryo transfer, postponing instead it to a subsequent unstimulated cycle. Although this strategy may reduce the detrimental effect LFEP may have on cumulative ART pregnancy rates, it may also frustrate couples who wish to become pregnant as soon as possible.

With the intent of minimizing potentially-avoidable treatment delays, an increasing number of researchers are proposing that physicians revisit their current ovarian stimulation regimens. One strategy which may reduce the incidence of LFEP is to decrease the dose of gonadotropins administered at the end of stimulation (i.e. a stepdown protocol). A similar approach, using corifollitropin alpha (CFA), has also been recently advanced, taking advantage of the stepdown-like pharmacodynamic profile of this compound.

In order to assess the clinical usefulness of these strategies, the investigators propose a single-center, open-label, paired, randomized trial. The main objective of this study is to assess the changes in the endometrial gene expression profile on the day of fresh embryo transfer according to the type of gonadotropins administered for ovarian stimulation. In summary, all consenting subjects will first undergo an endometrial biopsy seven days after the luteinizing hormone peak in an unmedicated natural cycle. This biopsy will serve as the baseline endometrial biopsy (natural cycle biopsy) for a gene expression analysis. Following this baseline biopsy, subjects will be randomly allocated to a specific type of ovarian stimulation regimen in order to later perform a second endometrial biopsy, this time five days after oocyte retrieval (stimulated cycle biopsy). Subjects will be randomized to administer, on the third day of their menstrual cycle, either a single dose of 150 IU of CFA (study arms 1A and 1B) or a fixed daily dose of 200 or 300 IU of recombinant follicle stimulating (rFSH, study arm 2). On the eighth day of stimulation, it is expected that 15% to 30% of all subjects who performed CFA will have reached the follicular development criteria for final oocyte maturation and ovulation triggering.

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.
24

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 Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Portugal
      • Lisboa, Portugal
        • Instituto Valenciano de Infertilidade

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

18 years to 42 years (Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Informed consent form (ICF) dated and signed.
  2. Age: ≥18 and ≤42 years old.
  3. AFC <20.
  4. AMH <2.5 ng/mL, performed in the 12 months prior to inclusion.
  5. Body Mass Index (BMI): ≥18.5 Kg/m2 and <30 Kg/m2.
  6. Weight: ≥50 kg and <80 kg.
  7. First or second ART cycle (with pregnancy wish and planned for single blastocyst transfer) at the study site, or fertility preservation cycle.
  8. Regular menstrual cycles (between 22 and 35 days).
  9. Two ovaries present.

Exclusion Criteria:

  1. Simultaneous participation in another clinical study.
  2. Previous history of poor ovarian response (<4 oocytes retrieved) with a maximal dose of OS (≥300 IU/day) or OHSS, regardless of gonadotropin dose.
  3. Known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the endometrial cavity, Asherman's syndrome, thrombophilia or endometrial tuberculosis).
  4. Repeated miscarriages (>2 previous biochemical pregnancies or >2 spontaneous miscarriages).
  5. Recurrent implantation failure (>3 failed cycles with good quality embryos).
  6. Polycystic ovary syndrome (PCOS).
  7. Tumours of the ovary, breast, uterus, pituitary or hypothalamus.
  8. Abnormal (not menstrual) vaginal bleeding without a known/diagnosed cause.
  9. Ovarian cysts or enlarged ovaries.
  10. Fibroid tumours of the uterus incompatible with pregnancy.
  11. Malformations of the reproductive organs incompatible with pregnancy.
  12. Primary gonadal failure.
  13. Renal impairment defined as estimated glomerular filtration rate of 90 ml/min/1.73 m2 determined by the Modified Diet and Renal Disease (MDRD) equation at screening.
  14. Previous antibiotic hypersensitivity reactions (streptomycin and/or neomycin).
  15. Risk factors for thromboembolic events, such as a personal or family history, severe obesity or thrombophilia.
  16. Moderate or severe hepatic impairment.
  17. Untreated and uncontrolled thyroid dysfunction.
  18. Current use of oral contraceptive, anti-depressants, anti-psychotics, steroids, anti-epileptics or chemotherapy.
  19. Administration of exogenous Estradiol (E2), Progesterone (P4) or gonadotropins in the preceding menstrual cycle.
  20. Active female smoking.
  21. Acceptors of donated oocytes/embryos.
  22. Ongoing pregnancy.
  23. Women who have previously enrolled in the trial.
  24. Those unable to comprehend the investigational nature of the proposed study.

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: Diagnostic
  • 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.
Experimental: CFA plus step-down rFSH (1A)

A single dose of 150 IU of CFA followed by daily rFSH will be administered. The initial rFSH administration will be dosed between 100 IU and 200 IU according to the following criteria:

  • 200 or 300 IU: <3 follicles above 13 mm visible on transvaginal ultrasound;
  • 150 IU, >2 follicles above 13 mm and circulating day-8 follicle-stimulating hormone (FSH) levels ≤20 IU/mL.
  • 100 IU, >2 follicles above 13 mm and circulating day-8 FSH levels >20 IU/mL;

Subjects will perform a step-down daily rFSH dose (fixed decreases in the dosing of 25 IU/day) until the triggering criteria are met or a minimum of 50 IU/day is reached. Subjects with <3 follicles above 13 mm visible will maintain 200 IU/day of rFSH until this criterion is met, initiating a fixed 25 IU/day stepdown protocol only from then onwards.
Drug: CFA
Long-acting exogenous ovarian stimulation
Other Names:
  • Corifollitropin alpha
Drug: rFSH
Daily rFSH
Other Names:
  • Puregon
  • Follitropin beta
Procedure: Step-down daily rFSH dose
The dose of daily rFSH is progressively reduced
Experimental: CFA plus fixed daily dose rFSH (1B)
A single dose of 150 IU of CFA followed by a fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation
Drug: CFA
Long-acting exogenous ovarian stimulation
Other Names:
  • Corifollitropin alpha
Drug: rFSH
Daily rFSH
Other Names:
  • Puregon
  • Follitropin beta
Procedure: Fixed daily rFSH dosing protocol of 200-300 IU
The dose of daily rFSH is fixed at 200 or 300 IU
Active Comparator: Fixed daily dose rFSH only
A fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation
Drug: rFSH
Daily rFSH
Other Names:
  • Puregon
  • Follitropin beta
Procedure: Fixed daily rFSH dosing protocol of 200-300 IU
The dose of daily rFSH is fixed at 200 or 300 IU

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
Endometrial gene expression signature on the day of embryo transfer
Time Frame: 7 days after the last day of ovarian stimulation
RNA sequencing of specimen of endometrium
7 days after the last day of ovarian stimulation

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
Measure Description
Time Frame
Serum concentrations of progesterone from the start of stimulation until the day of embryo transfer
Time Frame: 3 weeks
Measurement of serum circulating progesterone levels (in ng/mL)
3 weeks

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.
Instituto Valenciano de Infertilidade de Lisboa

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.
Merck Sharp & Dohme LLC

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: Samuel Santos-Ribeiro, MD PhD, Instutito Valenciano de Infertilidade de Lisboa

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 29, 2020

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.
May 22, 2023

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.
May 22, 2023

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).
November 26, 2018

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.
November 27, 2018

First Posted (Actual)

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.
November 28, 2018

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.
June 1, 2023

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.
May 31, 2023

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.
May 1, 2023

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.
  • 1806-LIS-044-SD

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

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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