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Effect of Different Ovarian Stimulation Protocols on Endometrial Receptivity

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ClinicalTrials.gov Identifier: NCT03755973
Recruitment Status : Not yet recruiting
First Posted : November 28, 2018
Last Update Posted : February 27, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Instituto Valenciano de Infertilidade de Lisboa

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Infertility, Female Endometrial Diseases Drug: CFA Drug: rFSH Procedure: Fixed daily rFSH dosing protocol of 200 IU Procedure: Step-down daily rFSH dose Phase 4

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 1, 2 and 3) or a fixed daily dose of 200 IU of recombinant follicle stimulating (rFSH, study arm 4). 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. These patients will be subclassified as study arm 1. The remaining patients who performed CFA and that will not be ready for triggering after eight days of ovarian stimulation will be randomized a second time to administer further daily follitropin beta either in a stepdown protocol (study arm 2) or a fixed daily dose of 200 IU (study arm 3).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: All consenting subjects will first undergo an endometrial biopsy seven days after the luteinizing hormone (LH) peak in an unmedicated natural cycle. This biopsy will serve as the baseline endometrial biopsy (natural cycle biopsy) for the gene expression signature analysis. Following this baseline biopsy, the subjects will be randomly allocated to a specific type of ovarian stimulation regimen in order to later perform some second endometrial biopsy, five days after oocyte retrieval (stimulated cycle biopsy).
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: How do Different Ovarian Stimulation Protocols Affect Endometrial Receptivity During a Fresh In-vitro Fertilization Attempt
Estimated Study Start Date : May 1, 2019
Estimated Primary Completion Date : November 30, 2019
Estimated Study Completion Date : January 31, 2020

Arm Intervention/treatment
Experimental: CFA only
A single dose of 150 IU of CFA will be administered as ovarian stimulation
Drug: CFA
Long-acting exogenous ovarian stimulation
Other Name: Corifollitropin alpha

Experimental: CFA plus fixed daily dose rFSH
A single dose of 150 IU of CFA followed by a fixed daily rFSH dosing protocol of 200 IU will be administered as ovarian stimulation
Drug: CFA
Long-acting exogenous ovarian stimulation
Other Name: Corifollitropin alpha

Drug: rFSH
Daily rFSH
Other Names:
  • Puregon
  • Follitropin beta

Procedure: Fixed daily rFSH dosing protocol of 200 IU
The dose of daily rFSH is fixed at 200 IU

Experimental: CFA plus step-down rFSH

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 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 Name: 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

Active Comparator: Fixed daily dose rFSH only
A fixed daily rFSH dosing protocol of 200 IU will be administered as ovarian stimulation
Drug: rFSH
Daily rFSH
Other Names:
  • Puregon
  • Follitropin beta

Procedure: Fixed daily rFSH dosing protocol of 200 IU
The dose of daily rFSH is fixed at 200 IU




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Serum concentrations of estradiol on the day of embryo transfer [ Time Frame: 7 days after the last day of ovarian stimulation ]
    Measurement of serum circulating estradiol levels (in pg/mL)

  2. Serum concentrations of progesterone on the day of embryo transfer [ Time Frame: 7 days after the last day of ovarian stimulation ]
    Measurement of serum circulating progesterone levels (in ng/mL)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥18 and <36 years old
  • antral follicle count ≥5 and <20
  • anti-mullerian hormone levels ≥1.1 ng/mL and <2.5 ng/mL
  • Body mass index ≥18.5 Kg/m2 and <30 Kg/m2
  • Weight ≥50 kg and <80 kg
  • First or second ART cycle
  • Regular menstrual cycles (between 22 and 35 days)
  • Gonadotropin-releasing hormone (GnRH) antagonist suppression protocol
  • Two ovaries present
  • Current pregnancy wish
  • Planned for single blastocyst transfer
  • Signed informed consent

Exclusion Criteria:

  • Previous history of poor ovarian response (<4 oocytes retrieved) with a maximal dose of ovarian stimulation (≥300 IU/day) or ovarian hyperstimulation syndrome, regardless of gonadotropin dose
  • Known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the endometrial cavity, Asherman's syndrome, thrombophilia or endometrial tuberculosis)
  • Repeated miscarriages (>2 previous biochemical pregnancies or >2 spontaneous miscarriages)
  • Recurrent implantation failure (>3 failed cycles with good quality embryos)
  • Polycystic ovarian syndrome
  • Untreated thyroid dysfunction
  • Administration of exogenous E2, P4 or gonadotropins in the preceding menstrual cycle
  • Active female smoking
  • Acceptors of donated oocytes/embryos
  • Ongoing pregnancy
  • Women who have previously enrolled in the trial
  • Those unable to comprehend the investigational nature of the proposed study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03755973


Contacts
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Contact: Samuel Santos-Ribeiro, MD PhD +351218503210 samuel.ribeiro@ivirma.com

Sponsors and Collaborators
Instituto Valenciano de Infertilidade de Lisboa
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Samuel Santos-Ribeiro, MD PhD Instutito Valenciano de Infertilidade de Lisboa

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Responsible Party: Instituto Valenciano de Infertilidade de Lisboa
ClinicalTrials.gov Identifier: NCT03755973     History of Changes
Other Study ID Numbers: 1806-LIS-044-SD
First Posted: November 28, 2018    Key Record Dates
Last Update Posted: February 27, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Infertility
Infertility, Female
Uterine Diseases
Genital Diseases, Male
Genital Diseases, Female